Devices and methods for light delivery

ABSTRACT

Provided are conformable light delivery devices for increasing light penetration depth and related methods. The device may comprise a microarray of tissue penetrating members, each member having a distal end and a proximal end, wherein the tissue penetrating members are at least partially optically transparent to provide optical transmission through a surface that extends between the distal and proximal ends of each tissue penetrating member and a substrate that supports the tissue penetrating members, wherein the substrate is optionally a flexible substrate.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and priority to U.S. ProvisionalPatent Application No. 62/673,305 filed May 18, 2018, which isspecifically incorporated by reference in its entirety to the extent notinconsistent herewith.

BACKGROUND OF INVENTION

Provided herein are various devices and methods for providing controlledlight delivery in a manner that increases light penetration depthrelative to a surface, including in biological tissues. It can beparticularly challenging to provide reliable and uniform light intensitybeneath a tissue surface without surgical implantation and/or invasiveintroduction of light sources, particularly as the desired opticalwavelengths may tend to have extremely limited penetration depth.Furthermore, biological surfaces tend to have complex surface shapes,including time-dependent and force-dependent shapes, such as for theskin.

There are other applications where controlled light delivery is desired.For example, in the context of interventional cardiology—UVA-1 orvisible light LEDs have the potential to offer therapeutic value. Forinstance, UVA-1 and red-light LEDs (wavelength 600-700 nm) have beenshown to cause vasodilation in blood vessels. Thus, deployment ofmicro-LEDs on balloon catheters, guidewires, and stents (peripheral,venous, arterial) would hold potential value as new therapeutic modalityto prevent vessel stenosis or to increase flow transiently in thesetting of acute ischemia.

Furthermore, phototherapy is the standard of care for a wide range ofdermatological conditions, with an estimated (as of 2016), totalmarket/device size of about $500 million USDs. The opportunity here isto provide a significant improvement over existing phototherapy systemsto enable the faster and more efficacious treatment of skin diseases. Inaddition, the ability to deliver therapeutic light deeper—conditionspreviously not conducive to phototherapy (e.g. scars, keloids) isrelevant.

For at least these reasons, there is a need for augmented forms of lighttherapy that is more efficacious, faster in delivering therapeuticresponse, affordable, and that can be used outside the clinical setting,such as for home use. Such a system provides a significant therapeuticadvance, including ensuring reliable and relatively deep light deliveryin a package that is easy-to-use and comfortable, thereby increasing thelikelihood of patient protocol adherence.

SUMMARY OF THE INVENTION

The devices provided herein address the above problems by providingspecially configured light waveguides in the form of tissue penetratingmembers that can conform to various curvilinear systems. For example,flexible optical light sources may be supported by a top surface of aflexible substrate. The bottom surface of the flexible substrate maysupport a microarray of tissue penetrating members. The optical lightsources may be in optical communication with the microarray of tissuepenetrating members, so that during use the activated light sourcesprovide light to the penetrating members, which in turn provide light tothe surrounding tissue.

The devices provided herein may be described as having a light sourcecomponent and a microarray of tissue penetrating member component. Thelight source component may be reusable, and the tissue penetratingmember component single use or disposable, such as by a removableconnection to the substrate that supports the components.

The devices and methods are particularly suited for providing lightpenetration through otherwise optically challenging surfaces, includingthe skin, an internal tissue, a blood vessel, and any other tissue wherecontrolled light intensity is desired.

The devices provided herein offer a completely new treatment modalityfor a range of medical conditions by allowing for deeper delivery oftherapeutic light. The technology can be utilized as a single standalonesystem (therapeutic LEDs in the UV, visible light, IR, and NIRspectrums) or as an adjuvant (microneedles alone) to enhance lightpenetration from a separate light source. Thus, this technology can beused as a disposable component for single phototherapy sessions.

The underlying concepts can be deployed in interventional cardiology orimplantable systems to treat various conditions where deeper delivery oftherapeutic light would be beneficial.

Unique aspects of the devices and methods provided herein includerelatively stiffer needles, such as made of PLGA, to facilitate enhancedpenetration in disease, thickened skin. Furthermore, UV delivery isenhanced; although the devices and methods provided herein arecompatible with a range of wavelengths, including visible light. UVlight, however, has demonstrated far higher dissipation with depthcompared to light in the visible portion of the spectrum.

In addition, the devices provided herein are flexible—where the PLGAmicroneedles can bend allowing conformable contact with the skin and canbe described as being an integrated system. For example, a top layer ofLEDs embedded within a flexible substrate that rests on top of themicroneedles. This enables a complete end-to-end system.

Provided is a conformable light delivery device for increasing lightpenetration depth comprising: a microarray of tissue penetratingmembers, each member having a distal end and a proximal end, wherein thetissue penetrating members are at least partially optically transparentto provide optical transmission through a surface that extends betweenthe distal and proximal ends of each tissue penetrating member; and asubstrate that supports the tissue penetrating members. any of thesubstrates described herein may be characterized as a flexible substrateto Also provided is a conformable light delivery device for increasinglight penetration depth comprising: a microarray of tissue penetratingmembers having a distal end and a proximal end, wherein the tissuepenetrating members are at least partially optically transparent over arange of wavelengths to provide optical transmission through a surfacethat extends between the distal and proximal ends of each tissuepenetrating member; a flexible substrate having a top surface and abottom surface, wherein the bottom surface supports the tissuepenetrating members; a plurality of optical sources supported by theflexible substrate top surface; an electronic circuit electricallyconnected to the plurality of optical sources; and an encapsulationlayer that at least partially encapsulates the plurality of opticalsources and the electronic circuit.

Also provided is a method of using any of the devices described hereinto provide light to a tissue. Also provided is a method of making any ofthe devices described herein.

Representative examples of the instant invention include, but are notlimited to:

1. A conformable light delivery device for increasing light penetrationdepth in a tissue comprising: a microarray of tissue penetratingmembers, each member having a distal end and a proximal end, wherein thetissue penetrating members are at least partially optically transparentto provide optical transmission through a surface that extends betweenthe distal and proximal ends of each tissue penetrating member; and asubstrate that supports the tissue penetrating members, wherein thesubstrate is optionally a flexible substrate.

2. The light delivery device of example 1, further comprising an opticalsource in optical communication with the microarray of tissuepenetrating members.

3. The light delivery device of example 2, wherein the optical sourcecomprises a plurality of LEDs.

4. The light delivery device of any of examples 2 or 3, wherein theoptical source has an emission maximum in a visible range of theelectromagnetic spectrum.

5. The light delivery device of any of examples 2 or 3, wherein theoptical source has an emission maximum in a UV range of theelectromagnetic spectrum.

6. The light delivery device of example 5, wherein the emission maximumis between 100 nm and 400 nm.

7. The light delivery device of any of examples 2-6, wherein the opticalsource delivers at least 0.1 mW/cm² and/or at least 10 mJ/cm² to atissue during use.

8. The light delivery device of any of examples 1-7, wherein themicroarray and optical source are integrated or removably connected toeach other.

9. The light delivery device of any of examples 2-8, wherein the opticalsource is at least partially encapsulated in a transparent encapsulationlayer.

10. The light delivery device of any of examples 1-9, wherein themicroarray of tissue penetrating members are configured to penetrateskin during use and to increase a penetration depth of UV light intotissue by at least a factor of 1.1 compared to UV light exposed to theskin without the microarray of tissue penetrating members.

11. The light delivery device of any of examples 1-10, wherein eachtissue penetrating member transmits at least 90% of ultraviolet light ora desired subrange thereof.

12. The light delivery device of any of examples 1-11, wherein themicroarray of tissue penetrating members corresponds to an array ofmicroneedles

13. The light delivery device of example 12, wherein the microneedleshave a geometrical shape that is tetrahedral, square, pyramidal orconical.

14. The light delivery device of any examples 1-13, wherein the tissuepenetrating members have a length that is greater than or equal to 100μm and less than or equal to 10 mm and/or a pitch distance that isgreater than or equal to 100 μm and less than or equal to 1 mm.

15. The light delivery device of any of examples 1-14, wherein thetissue penetrating members have an optical property that is opticallymatched to an optical light source, wherein the optical property isselected from the group consisting of: optical transmission/output lightspectrum; index of refraction; scattering, absorption, emissivity,fluorescence, heat generation; and thermal relaxation time of tissue.

16. The light delivery device of any of examples 1-15, wherein thetissue penetrating members are tapered, with a maximum width at theproximal end and a minimum width or a tip at the distal end.

17. The light delivery device of example 16, wherein the minimum widthis between 5 μm and 50 μm and the maximum width between 100 μm and 1 mm

18. The light delivery device of any of the above examples, whereinultra-violet light is transmitted from the tissue penetrating membersthrough all side surfaces and the distal end to tissue surrounding thetissue penetrating members.

19. The light delivery device of any of the above examples, wherein thetissue penetrating members are formed of a biocompatible material,wherein the biocompatible material optionally comprises a polymer.

20. The light delivery device of any of the above examples, wherein thetissue penetrating members are formed of a material selected from thegroup consisting of: poly(D,L-lactide-co-glycolide) (PLGA), polylacticacid, poly-methyl-methacrylate, PDMS, and carboxymethyl cellulose.

21. The light delivery device of any of the above examples, wherein thedevice is flexible with a bulk bending stiffness selected so that thedevice is capable of conforming to a tissue surface during a lighttherapy application to reduce surface reflection and increase lightdelivery to a target.

22. The light delivery device of example 21, wherein the reduced surfacereflection is by the substrate having a composition that provides andindex of refraction that is within 10% of an index of refraction of amaterial from which the tissue penetrating members are formed.

23. The light delivery device of any of the above examples, furthercomprising an optical dispersion element in optical communication withthe tissue penetrating members to increase light dispersion and increaselight intensity uniformity to a tissue that surrounds the tissuepenetrating members during use, wherein the optical dispersion elementcomprises one or more of: a roughened tissue penetrating member surface;an optical coating; a diffraction grating; a waveguide; achemically-modified tissue penetrating member surface; a patternedoptically opaque layer; lenses; or upconverting or downconvertingphosphors.

24. The light delivery device of any of the above examples, having alight transmission footprint that is greater than or equal to 0.2 cm².

25. The light delivery device of any of the above examples, wherein thesubstrate has a bottom surface that supports the microarray of tissuepenetrating members and a top surface that supports a plurality ofoptical sources.

26. The light delivery device of example 25, wherein the microarray oftissue penetrating members are optically aligned with the plurality ofoptical sources to provide substantially uniform light intensity to atissue that surrounds the microarray of tissue penetrating members.

27. The light delivery device of any of the above examples, wherein themicroarray of tissue penetrating members is formed from a microarraymaterial having an index of refraction that is matched to an index ofrefraction of the substrate.

28. The light delivery device of any of the above examples, wherein thetissue penetrating members are solid.

29. The light delivery device of any of 1-27, wherein the tissuepenetrating members are: hollow; solid with cavities; or solid withembedded liquid.

30. The light delivery device of any of examples 1-29, furthercomprising a bioactive agent.

31. The light delivery device of example 30, wherein the bioactive agentcomprises a coating on at least a portion of a surface of thepenetrating members.

32. The light delivery device of any of the above examples, having atissue penetrating member occupancy fraction (area of member base toarea of substrate) that is greater than or equal to 10%.

33. The light delivery device of any of the above examples, wherein thetissue penetrating members have an effective Young's modulus selected towithstand stresses during insertion through a tissue surface withoutsubstantial deformation in a direction that decreases penetration depthin the tissue.

34. The light delivery device of any of the above examples, wherein thedevice further comprises a bioactive agent releasably connected to themicroarray of tissue penetrating members, wherein the bioactive agent isactivated by light transmitted by the microarray of tissue penetratingmembers.

35. The light delivery device of any of the above examples, wherein thedevice is integrated in a stent, a guidewire, a catheter, a ballooncatheter for use in a blood vessel; a subdermal implant; an orthopedicimplant, a prosthesis, or a neurological implant.

36. The light delivery device of example 35, wherein the device is aconformable intra-arterial or intra-venous device and comprises aplurality of LEDs in optical communication with the microarray of tissuepenetrating members.

37. The light delivery device of example 36, wherein the LEDs areUV-emitting LEDs.

38. The light delivery device of example 37, wherein UV light emitted bythe UV-emitting LEDs is able to cause vasodilation in blood vessels.

39. The light delivery device of example 36, wherein the tissuepenetrating members have a length that is greater than or equal to 10 μmand less than or equal to 100 μm, a pitch distance that is greater thanor equal to 100 μm and less than or equal to 500 μm, and a maximum widthbetween 50 μm and 100 μm.

40. The light delivery device of any of the above examples, furthercomprising a light intensity modulator for controlling light intensityas a function of depth from a tissue surface.

41. The light delivery device of example 40, wherein the light intensitymodulator comprises a non-transparent coating extending from the tissuepenetrating members' proximal end to reduce optical light intensity to atissue surface region.

42. The light delivery device of example 41, wherein the non-transparentcoating reduces UV light transmission and the tissue surface regioncorresponds to an epidermal layer.

43. The light delivery device of example 40, wherein the light intensityoutput is focused toward or at the distal end of the tissue penetratingmembers.

44. The light delivery device of any of the above examples, wherein thesubstrate is formed of a therapeutically-beneficial material or of atherapeutic agent connected to, or supported by, the substrate.

45. The light delivery device of example 44, wherein thetherapeutically-beneficial material comprises silicone and thetherapeutic benefit is improvement in scar appearance.

46. The light delivery device of any of the above examples, wherein thesubstrate further comprises a substrate component that improves lightdelivery, wherein the substrate component comprises one or more ofglycerol or perfluorodecalin.

47. A conformable light delivery device for increasing light penetrationdepth in a material comprising: a microarray of tissue penetratingmembers having a distal end and a proximal end, wherein the tissuepenetrating members are at least partially optically transparent over arange of wavelengths to provide optical transmission through a surfacethat extends between the distal and proximal ends of each tissuepenetrating member; a flexible substrate having a top surface and abottom surface, wherein the bottom surface supports the tissuepenetrating members; a plurality of optical sources supported by theflexible substrate top surface; an electronic circuit electricallyconnected to the plurality of optical sources; and an encapsulationlayer that at least partially encapsulates the plurality of opticalsources and the electronic circuit.

48. The conformable light delivery device of example 47, wherein themicroarray and flexible substrate are disposable and replaceable.

49. A method of providing light to a tissue, the method comprising thesteps of: providing any of the devices of examples 1-48; conformallycontacting the microarray with a tissue surface; inserting at least aportion of the microarray of tissue penetrating members into the skin;transmitting light through the flexible substrate and the microarray oftissue penetrating members to a tissue that surrounds the microarray oftissue penetrating members.

50. The method of example 49, wherein the tissue surface corresponds toa skin surface.

51. The method of example 49 or 50, wherein the tissue surface comprisesa curved surface.

52. The method of any of examples 49-51, wherein the transmitting stepcomprises: energizing a plurality of LEDs connected to the substratesurface, wherein the LEDs have an emission maximum in the UV range or avisible portion of the electromagnetic spectrum.

53. An injectable therapeutic light delivery device comprising: asubstrate; a tissue penetrating member having a proximal end and adistal end, wherein the proximal end is supported by the substrate; aplurality of light sources optically dispersed along a member wall thatextends between the member proximal and distal ends; wherein the tissuepenetrating member and plurality of light sources are configured topenetrate a tissue to provide controlled subsurface light intensity totissue that surrounds the tissue penetrating member.

54. The device of example 53 wherein the tissue penetrating membercomprises a needle.

55. The device of example 54, wherein the needle comprises an opticallynon-transparent material, including a metal, and the optical lightsources are LEDs that are distributed on a tissue-facing surface of theneedle.

56. The device of example 55, wherein the LEDs are UV-emitting LEDs.

57. The device of any of examples 53-56 configured to treat cancer,including cutaneous T-cell lymphoma.

58. The device of any of examples 53-57, wherein the light delivery isof UVA or UVB light at a tissue depth that is greater than or equal to 1cm.

59. The device of any of examples 53-58, comprising a plurality oftissue penetrating members, wherein each tissue penetrating member has aplurality of light sources optically dispersed along the member wallthat extends between the member proximal and distal ends.

Without wishing to be bound by any particular theory, there may bediscussion herein of beliefs or understandings of underlying principlesrelating to the devices and methods disclosed herein. It is recognizedthat regardless of the ultimate correctness of any mechanisticexplanation or hypothesis, an embodiment of the invention cannonetheless be operative and useful.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1F. Scheme and design of an integrated wearable light(including for UVA-1) therapy device. FIG. 1A: Exploded scheme of theintegrated wearable device combining a UVA LED patch with an array oftissue penetrating members formed of PLGA microneedles as a light guide.The LED patch comprises a 3 by 3 UVA LED array on a flexible polyimidesubstrate printed with copper circuits. The PDMS encapsulated LED patchis integrated with the biocompatible PLGA microneedle array. FIG. 1B: Aphotograph of the integrated device with an active area (i.e., with LEDand microneedles) of about 7 by 7 mm. FIG. 1C: The cross-sectional viewof the integrated device with LEDs powered on (bottom) or off (top).Scale bar is 5 mm. FIG. 1D: Schematic close up (not to scale) of aside-view cross-section of the substrate and tissue penetrating members,with various optional optical components to control optical parameters.FIG. 1E: Schematic of a top-down view cross-section at the substratesurface illustrating an array whose geometry and configuration providesfor a desired footprint, in both an optical aspect and a physicalaspect. FIG. 1F: schematic illustration of various geometry of themicroneedles, including tetrahedral, square, pyramidal and conical. Acommon feature is the distal end of the microneedle goes to a minimum tofacilitate tissue penetration and minimize tissue damage. The taperangle of the microneedles are exaggerated for clarity, and can be muchmore gentle, like a hypodermic needle, with a distal portion that tapersand a proximal portion that has substantially uniform cross-sectionaldimensions.

FIGS. 2A-2D. Optical characterization of the LED patch. FIG. 2A: Aphotograph of the compact 3 by 3 array of optical sources, in thisexample UVA-1 LEDs. FIG. 2B: The dependence of output optical irradianceand temperature increase on driving current of the UVA-1 LED patch. FIG.2C: An optical image of a 1 mm-thick Dylight 350-containing Agarose gelplaced on top of the LED patch. The dashed boxes indicate the locationof the 3 by 3 LED array. FIG. 2D: Measured light intensity distributionalong 9 randomly selected lines inside the LED area (the boxed area inFIG. 2C), indicating a substantially uniform light intensity over thewhole LED patch.

FIGS. 3A-3D. Configurations of the PLGA microneedle arrays and theirpenetration in real skin samples. FIG. 3A: Microscopic images ofpyramidal PLGA microneedle arrays with 1 mm length and variouscombinations of base size and spacing. From left to right, the base size(μm) and spacing (μm) for the arrays are 200/100, 400/200, 300/100, and400/200, respectively. The MN tip radius is 10-20 μm. Scale bar=1 mm.FIG. 3B: A microscopic image of the trypan blue stained pig skin afterPLGA MN insertion. FIG. 3C: Cross sectional magnetic resonance imaging(MRI) of PLGA MNs inserted in pig skin. FIG. 3D: The statistics ofinsertion depth of MNs (0.73±0.04 mm, n=10) in pig skin based on MRIimage analysis (FIG. 3C). The MNs used for (FIGS. 3B-3D) are pyramidalshaped needles with base size=400 μm, spacing=200 μm, and length=1 mm.

FIGS. 4A-4B. Optical visualization of the enhanced light dissipation inskin mimicking phantom via PLGA MNs. FIG. 4A: (Left) A photograph of agelatin skin phantom block placed on top of a PLGA plate without MNs.(Right) An image taken without ambient light to visualize thedissipation of 400 nm light (from a collimated LED light source placedunderneath) in skin phantom. FIG. 4B: (Left) A photograph of a gelatinskin phantom block with a PLGA MN array inserted. (Right) An imagevisualizing the dissipation of 400 nm light (from a collimated LED lightsource placed underneath) in skin phantom. Inset shows the microscopicimage of the same sample. Scale bar=1 mm. Each white arrow indicates asingle needle.

FIGS. 5A-5F. Monte Carlo simulation of light dissipation in skin. Insilico experiment of normalized light irradiance distribution (inmW/cm²) in a single microneedle unit cell (FIGS. 5B, 5C) and an array ofmicroneedles (FIGS. 5E, 5F), as well as the standard care approachwithout needles (FIGS. 5A, 5D). The light irradiance at the top of skinis 20 mW/cm² and the incident angle is either 0 deg. (FIGS. 5B, 5E) or±45 deg. (FIGS. 5C, 5F). The microneedles have dimensions of 0.7 mmlength, 400 μm base size and 200 μm spacing. In (FIGS. 5A-5C), the lightenters the microneedles or skin from a 400 μm by 400 μm area.

FIG. 6. Light irradiance (in mW/cm²) at various depths in the skin(standard care versus microneedle (MN) case) calculated based on MonteCarlo simulation. The light intensity at the top of skin is set as 20mW/cm² and the incident angle is either 0 deg. or ±45 deg. The MNs havedimensions of 1 mm length, 400 μm base size and 200 μm spacing. Note thecrossover occurs at around 200 μm depth.

FIGS. 7A-7D. Demonstration of the flexible, wearable integrated lighttherapy device. FIG. 7A: A photograph of an array of UVA-1 LEDs on athin (12.5 μm), flexible polyimide substrate. FIG. 7B: Photographs ofPLGA MNs with a highly flexible handling layer as well as rigid needles.Scale bar=1 mm. FIGS. 7C, 7D: Photographs of a prototype, integratedlight therapy device on the arm of a human subject.

FIG. 8. Traditional NBUVB and Experimental System. Current systems havelimited ultra-violet light penetration (compare top left panelpenetration depth 801 with top right panel penetration depth 802). Thetop layer of skin in psoriasis is extra-thickened (see bottom panel),which limits the penetration of the ultra-violet light that treatspsoriasis. The devices provided herein are soft and flexible, allowingthe device to wrap around a psoriasis spot (e.g., conformal contact) forbetter light delivery. Also, the devices provided herein can have tinymicro-needles that allow deeper penetration of therapeutic light. Theycreate optical channels in the skin.

FIG. 9. Demonstration of LEDs (670 nm) in a flexible substrate, usefulfor facilitating conformal contact to a tissue surface, including acurvilinear surface. See, e.g., Kim, et al. Nat. Mater. 2010, 9, 929.

FIG. 10. Illustration of traditional UV phototherapy limited bypenetration depth compared to a device provided herein having tissuepenetrating members. The top layer of the LEDs of the device deliversuniform UV light but with the added advantage of microneedle waveguidesenabling deeper penetration of light when desired, as reflected byincreased penetration depth 130 between left and right panels. Arrays oflight sources, such as LEDs, facilitates controlled light exposuresurface area and also can provide very large surface area exposure, withcontrolled activation of the light sources also providing the ability toreliably illuminate relatively small surface areas.

FIG. 11. Depending on the simulation model, results indicate increasedlight dissipation along the z-axis with a microneedle waveguide (leftpanel). Without a microneedle waveguide, UVA1 penetrates only 200microns (right panel). Thus, the devices provided herein significantlyincrease UVA1 delivery in the z-axis, thereby increasing penetrationdepth.

FIG. 12. SEM images of tissue penetrating members, also referred hereinas microneedle waveguides, with a view of the entire array (left panel)and a close-up view of a portion of the array.

FIG. 13. Preliminary data using cadaveric porcine skin punctured bymicroneedles formed of PLGA.

FIG. 14. Agarose gel is used to model skin. Confocal microscopy showsincreased fluorescence (green light) created by the PLGA microneedles.

FIG. 15. Spectral results based on bench testing of Vishay UVA1 LEDsindicate the desired peak output of 360 nm.

FIG. 16. Device constructed with UVA1 LEDs (Vishay) coupled to PLGAmicroneedles. A 1×1 cm device demonstrates feasibility. Larger deviceswith more arrays of LEDs and microneedle waveguides with a larger totalsurface area are compatible. Scale bar is 2 mm, and bottom right is animage of the device held between fingers.

FIG. 17. Phototherapy: Wide Spectrum of Biological Activity over variouswavelengths, with associated potential harm.

FIG. 18. Schematic reproduction of biological effects of ultraviolet A(UVA)-1 on sclerotic skin diseases. IL, Interleukin; INF, interferon;MMP, matrix metalloproteinase; MSH, melanocyte-stimulating hormone;mRNA, messenger RNA; TGF, transforming growth factor.

FIG. 19. Absorption wavelength ranges for various biologicalconstituents and corresponding LED composition.

FIG. 20. Illustration of various optical light sources, including in theUVB (left—311 nm), UAA (right—365 nm) and visible (right) wavelengths.

FIG. 21. Silicone Sheeting: as a substrate that can facilitate improvedbiological outcome, such as for wound/scar healing.

FIG. 22. Plot of relative light intensity for UV light, with PDMS andwith PDMS and needles, with a corresponding reduction in light intensityof less than 15%, driven by 20 mA DC, compliance 4.0V.

FIG. 23. Therapeutic and/or optical enhancing substrate, including withoptical components to improve directed optical path for light betweenthe lights sources and underlying tissue penetrating members; UVC andUVB do not pass through the epidermis, and UVA only partially penetratesthe dermis.

FIG. 24. Depth and Spread of light of various wavelengths in tissue thatis the skin and underlying dermis.

FIG. 25. Table showing the average depth of the epidermis and dermislayers in various locations.

FIG. 26. UVA-1: Morphea penetration depth of 0.5 mm is less than typicallesion depths of about 3 mm.

FIG. 27. Unusual strategies for using indium gallium nitride grown onsilicon (111) for solid-state lighting.

FIG. 28. Selective depth-dependent heating.

FIG. 29. Microneedle designs.

FIGS. 30A-30E. Interventional Cardiology: UVA.

FIG. 31. The Runthrough NS (Terumo Interventional Systems, Somerset,N.J.).

FIG. 32. LLLT+Waveguides+Heat: Pain—demonstration on ankle.

FIGS. 33A-33G. LLLT+Waveguides+Heat: Pain.

FIG. 34. Low Level Light Therapy: Periorbital Rhytides.

FIG. 35. Use of optical modulator (top panel) to avoid UV exposure tothe proximal region of the penetrating member without impacting UVexposure at more distal regions, such as for the epidermis and dermallayers, respectively. Distribution of optical sources over a microneedlesurface (middle panel). The bottom panel illustrates sizes of theepidermis and dermis, and the need for the devices and methods of theinstant invention with respect to skin and underlying tissue.

FIG. 36. Fabrication scheme for an array of polymeric microneedles.

FIG. 37. Image of a 12×12 array of pyramidal microneedles, having alength of 1 mm, size of 400 μm, pitch 600 μm.

FIG. 38 is a plot of optical transmission as a function of wavelength(nm) for a 1 mm thick PLGA substrate.

FIG. 39 are images of arrays of microneedles having differentgeometrical configurations, with microneedle footprint fractions of 44%,56% and 64%.

FIG. 40 characterizes a UVA LED patch comprising 3×3 LEDs (1.6×1.6×1.4mm) (top left panel) having an emission spectrum illustrated in thebottom left panel. The top right panel is a temperature distributionplot. The bottom right panel is a plot of light intensity or temperaturechange as a function of current.

FIG. 41A is a light intensity map for a device having 3×3 array of LEDsover the footprint (scale bar is 1 mm). FIG. 41B is a plot of lightintensity along nine random lines in the patch area. FIG. 41C is aphotograph of the device accommodating a bending radius of about 3.5 mmwithout fracture. FIG. 41D is a plot of current versus voltage for aflat and a bent configuration (lines overlap), indicating bending doesnot affect electronic characteristics. FIG. 41E is a photograph of thedevice illustrating conformal characteristics, even to a curvilinearsurface.

FIG. 42 illustrates the extreme flexibility of the device, with lowstrains even in the curved conformation.

FIG. 43A is a photograph of the device on tissue (left panel—scale bar 5mm) with a close up view of the needle array (right panel—scale bar 500μm). FIG. 43B illustrates microneedle penetration in porcine skin (toppanel) and the measured insertion depth for various microneedles withinthe array (bottom panel).

FIG. 44 Monte Carlo simulations of illumination with and withoutmicroneedles (irradiation area 400 μm×400 μm; needle length 1 mm (singlemicroneedle) and length/size/pitch of 1000/400/600 μm for a microneedlearray. The top panel is a plot of irradiance as a function of tissuedepth and the bottom panel a plot of power as a function of depth,without and with microneedles (MN).

FIG. 45A is an experimental result of UV dye activation using UV lightin a gel skin phantom without (top panel) and with (bottom panel) amicroneedle array. FIG. 45B is an equivalent result with Monte Carlosimulations, thereby validating the computational model without (toppanel) and with (bottom panel) microneedle array.

FIG. 46A is a top view of a device laminated on ex-plant human skintissues. FIG. 46B is a side view of FIG. 46A. FIG. 46C-46D is a plot ofpercentage of cells positively identified as damaged as a function ofpower (13.5 J/cm² and 37.5 J/Cm², respectively) for a conventionaldevice (Lamp) and the instant microneedles (MN).

DETAILED DESCRIPTION OF THE INVENTION

In general, the terms and phrases used herein have their art-recognizedmeaning, which can be found by reference to standard texts, journalreferences and contexts known to those skilled in the art. The followingdefinitions are provided to clarify their specific use in the context ofthe invention.

“Conformable” refers to the ability of a device to undergo macroscopicdeformation so as to maintain intimate contact with a curvilinearsurface without generating substantial deformation forces on theunderlying surface. Such conformal contact is particularly challengingin the context of soft biological tissue that is readily deformed, evenunder relatively mild forces, including the skin. Such unwanteddeformation-generating forces can cause discomfort and irritation to theunderlying tissue. Such problems are avoided in the instant technologyby specially constructing the penetrating members, optical sources, andsupporting substrate, so that the device as a whole is flexible and ableto accommodate a wide range of complex shapes, thereby ensuringconformal contact is maintained. Such conformal contact may be furtherquantified in terms of no significant separation distance between thedevice and underlying surface. This helps ensure maximum light deliveryto the desired location, and avoids unwanted light leakage.Conformability may also be described in terms of the device being“flexible” and having a suitable bending modulus to provide desiredcurvature under an applied force. Conformable may be further describedin terms of desired mechanical properties such as bending stiffness andYoung's modulus such that air gaps are not present, thereby maximizinglight transfer to underlying tissue.

“Microarray” refers to a plurality of members, with each member havingat least one dimension that is less than 1 mm.

“Penetrating member” refers to a waveguide capable of being insertedinto tissue. As the devices presented herein are compatible with a rangeof tissues, the term “dermal penetrating member” can be anywherereplaced with the term “tissue penetrating member” (or vice versa), areflection that the penetrating members need not be limited topenetrating a dermal layer.

“Penetrating depth” refers to the distance beneath a surface that lightcan effectively travel.

“Optically transparent” refers to a material where light can pass.Depending on the application of interest, the light may be UV light,such as UVA or UVB light, or visible light, such as blue, red, green orany other color as desired. For example, in PDT applications, thedesired wavelength may correspond to the excitation wavelength of anoptically active agent.

“Encapsulation layer” refers to a material that at least partiallycovers another component, thereby protecting it and/or providing adesired mechanical parameter, such as bending stiffness, flexibility orsoftness.

“Substantially uniform” refers, in the context of light intensity, nosignificant hot spots of light intensity. The may be quantified, as amaximum light intensity that is less than 20% different from the averagelight intensity over the entire device illumination footprint.

Referring to the figures, FIG. 1A illustrates a conformable lightdelivery device 10 that can increase light penetration depth 130 in atissue 20 (see, e.g., FIG. 10, left panel without the instant devicehaving less penetration depth 130 compared to right panel where thepenetrating members significantly increase penetration depth 130). Amicroarray 30 of tissue penetrating members 40 that are at leastpartially optical transparent facilitate increased penetration depth oflight into tissue. Each penetrating member has a proximal end 60 and adistal end 50, where the distal end is directed toward deeper in thetissue and the proximal end extends from or is connected to a substrate80 that supports the microarray 30 of penetrating members 40. Betweenthe proximal and distal ends, a surface 70 can be configured tocontinuously transmit length over the longitudinal length or to modulateand control light delivery as a function of position along thelongitudinal length, such as increased light intensity introduced tosurrounding tissue toward the distal end compared to the proximal end.

An optical source 90 generates electromagnetic radiation over a desiredwavelength (FIGS. 17-19), including at an emission maximum 110 (see,e.g., FIG. 15). The optical light source 90 may comprise a plurality ofLEDs 100, including UVA and/or UVB LEDs, depending on the application ofinterest. The microarray of members 40 maybe integrated with the opticallight source 90 and corresponding electronic circuit 430. Alternatively,the portion of the device that comes into contact with biologicalmaterial (e.g., members 40 and substrate 80) may be removably connectedto other portions of the device (e.g., light source 90 and electronics430), for reuse of the optical portion, and disposal of themember/substrate portion. The connection may be via a removableadhesive, geometrical mating contact, and/or mechanical connector.

One or more encapsulation layers 120 may be used to protect underlyingcomponents, increase mechanical robustness and/or facilitateconformability with underlying tissue.

FIG. 1D is a cross-section of the device portion corresponding to thesubstrate 80 and penetrating members. The substrate 80 has a bottomsurface 240 that supports the penetrating members and an opposed topsurface 250 that faces toward optical source, such as the optical source90 illustrated in FIG. 1A. Members 40 may be defined in terms of alength 190, a pitch 200 (between center points of adjacent members) 201(between edges of adjacent members), a maximum width 205, a minimumwidth 206 or tip 210. The devices and related methods are compatiblewith application of a bioactive agent 300, illustrated in FIG. 1D as acoating on at least a portion on the surface of the penetrating member.The bioactive agent is accordingly in intimate contact with tissueadjacent the members, and can be a reliable means of introducingbioactive agent to tissue. The bioactive agent is optionallyphotoactive, so that light from the optical light source can be used toactivate the agent into an active agent. One example is a photodynamictherapy application, where an agent in combination with light having anactuating wavelength results in, for example, thermal generation, freeradical generation, isomerization, or release of an agent that can havean impact on a biological cell, bacteria or virus. The coating may coatthe entire outer surface 70 of the members, and may also be coated onthe substrate bottom surface. A substrate component 420 may be used toimprove light delivery. The substrate component is illustrated assupported by the top surface 250 of substrate 80, but may also bepositioned on the bottom surface 240, within the substrate 80 and/or inor on the member surface 70. For configurations where member is hollow,a component may be supported on an inner-facing and/or outer-facing wallof surface 70.

FIG. 1E is a schematic of a bottom view cross-section at the bottomsurface 240 of substrate 80. The proximal portion 60 of member 40 may bedescribed in terms of a member surface area 66. The substrate 80 mayalso be described in terms of a surface area, with, for convenience,FIG. 1F illustrated as rectangular with width 81 and length 82. Ofcourse, the invention is compatible with any of a wide range ofcross-sectional shapes of substrate 80 and members 40, with FIG. 1Fillustrating tetrahedral 150, square 160, pyramidal 170 and conical 180needles. The geometry may be described in terms of a “tissue penetratingmember occupancy fraction”=n*(proximal member surface area)/(surfacearea of substrate bottom surface), where n is the number of penetratingmembers in the array of microneedles, such as ranging from a relativelysparse array (e.g., about 0.05 to 0.2) to a relatively dense array(e.g., from about 0.5 to 0.9), and any subranges thereof.

FIG. 23 illustrates an optical dispersion element 220 configured foroptical communication with the tissue penetrating members (e.g.,“needles”) and optical light source (e.g., LEDs). The optical dispersionelements may be lenses positioned in optical alignment with underlyingmembers 40 to maximize light delivery to the members 40 and minimizelight that is directed to areas of substrate not having a correspondingunderlying member 40. Although FIG. 23 illustrates optical dispersionelement 220 as lenses, other types of dispersion elements arecompatible, including roughening (e.g., recess and/or relief features)of members and/or substrate, coatings, diffraction grating, waveguides,patterned optically opaque layer, phosphors. The optical dispersionelements can be positioned in the device (in an optical sense) betweenthe tissue and the light source, between the tissue and the membersand/or between the light source and the members.

FIG. 35 (top panel) illustrates a light intensity modulator 360 (e.g.,U.V. blocking coating) 362 (e.g., UV transparent coating). In thismanner, light intensity may be controlled as a function of distance fromthe bottom surface of the substrate. This can be useful, for example,where UV light is not desired at a skin surface, but is desired deeperin the tissue.

FIG. 35 (middle panel) illustrates a plurality of light or opticalsources 90 optically dispersed along the member wall an inner-facingmember wall surface 71. In this manner, further control of lightintensity as a function of position along a longitudinal axis 78, e.g.,tissue depth, is provided, such as so that only a distal portion, e.g.,a buried tissue layer physically separated by distance 3500 from thetissue surface, is exposed to light from the optical light source. Thedevices and methods provided herein can be configured to provide any ofa range of light exposure depths 3500, such as between 10 μm and 5 mm,20 μm and 4 mm, and any subranges thereof, such as between 20 μm andbetween 1 mm-2 mm.

Example 1: Devices and Methods for Light Delivery

The lack of availability, non-targeted nature, and inadequate lightdelivery into deep dermis of current light therapy devices underscorethe need for more accessible, selective, and high-efficacy light therapydevices. Using advanced techniques in flexible electronics, providedherein is a soft, conformable, and depth-modulated phototherapy device.The device's top layer has an array of light emitting diodes of variouswavelengths (e.g. UVA-1 LEDs with a spectral peak output of 360-nm),fully embedded within a substrate, including a flexible silicone. Thebottom layer includes a dense array of tissue penetrating members, suchas microneedles from bioresorbable poly-lactic-co-glycolic-acid (PLGA),a polymer enabling 99% of UVA transmittance, which create micro-channels700 μm for deeper UVA-1 delivery into the skin. Optical modeling,confirmed by confocal microscopy in agarose, demonstrates that the PLGAmicroneedle waveguides increase light transmission in deep skin below500 μm. The conformable nature of the device means the device canconform to any curvilinear body surface shape and be tailoredspecifically of any shape or size.

The methods and devices are compatible with a wide range ofapplications, including: Skin Diseases—Fibrotic diseases: morphea,keloids, scars; Neoplastic: cutaneous T-cell lymphomas, actinickeratoses, skin cancers (non-melanoma) Rheumatology: Systemic sclerosis;Cosmetic Dermatology: Skin rejuvenation; Collagen rejuvenation; Hairrejuvenation; Cardiology—Deployment of therapeutic LEDs (UVA-1, redlight, blue light) on cardiac stents, cardiac guidewires, cardiaccatheter balloons; Photodynamic Therapy—The microneedles may beimpregnated with photosensitizing topical medications that is thenactivated with light. For instance, one embodiment includes microneedleelution of amino-levulinic acid that is then subsequently activated byblue light.

The integrated wearable device is designed for augmented skin therapy,including in the comfort of a user's home. The flexible design allowsfor conformal contact with curvilinear skin. The device exposes lightlimited to the affected area, thereby decreasing or avoiding exposure tounwanted skin regions. Furthermore, the microneedle array facilitatesdeeper light delivery in the skin.

Broadly, the methods and devices provided herein augment the delivery oftherapeutic light. The primary mechanism is by increasing depthpenetration. Specifically, we demonstrate microneedles that areengineered specifically to enhance optical light delivery from anintegrated annealed top layer of LEDs embedded within a flexiblesubstrate. We have constructed a wearable phototherapy device forseveral sclerotic skin diseases such as morphea (localized scleroderma).This device combines a flexible array of UVA-1 LEDs (360 nm) and abioresorbable poly-lactic-co-glycolic-acid (PLGA) microneedle patch.Compared to the standard UVA-1 treatment of morphea by using mercury gaslamps with spectra filters, this wearable device provides moreaffordable therapy together with more effective light delivery in deepskin. It conforms to the curvilinear skin surface with a uniform outputdosage of 20 J/cm². The tunable shape and form factor of the patchavoids the exposure to unaffected area. Moreover, the PLGA microneedlearray, as light delivery device, delivers ˜400% more light into deepskin below 500 μm, whereas the standard care only treats superficiallesions due to the limited UVA-1 penetration depth. Such integrateddevices combining an LED array having any range of a specific wavelengthand bioresorbable microneedle light guides present a versatile andpotent platform for advanced skin therapy treatment, photodynamictherapy (including through the introduction of drug elution, such asfrom any of the tissue penetrating members), as well as fundamentalphotochemical study of biomolecules and living cells.

The photochemical and photobiologic process of biomolecules, cells, andtissues at specific wavelengths has laid the foundation of phototherapyin dermatology, oncology, and others.¹ For instance, UVA-1 (340-400 nm)has shown significant therapeutic benefits in treating several scleroticskin diseases such as morphea, systemic sclerosis and lichen sclerosis.²Morphea is a localized scleroderma characterized by excessive collagendeposition and thickened dermis (up to 2.6 mm)³. The underlyingmechanism for the light therapy is that UVA-1 leads to the upregulationof collagenase and IFNγ, leading to decreased collagen I, collagen III,and TGF-β expression.⁴ While considered as an effective approach, theconventional UVA-1 light therapy (or standard care) is conducted byusing mercury gas lamps with spectral filters. These apparatus, eitherphysician office-based or home unit, are not widely available orcost-effective, and unable to selectively treat the affected area. Thuslight dose is applied to both target skin lesions as well as normalskin, introducing a potential risk of undesirable photodamage oftissues. More importantly, the limited light penetration depth of UVA-1in skin (<150 μm) presents a grand challenge in light therapy,⁵prohibiting efficient treatment of morphea in deep skin.

The lack of availability, non-targeted nature, and inadequate lightdelivery into deep dermis underscore the need for more accessible,selective, and high-efficacy light therapy devices. We propose anintegrated, wearable device combining a flexible UVA-1 LED array withthe peak emission at 360 nm and a microneedle patch serving as lightguide. Taking advantage of the flexible design, it fits the curvilinearnature of human skin and can be readily used at home. The form factor ofthe whole device is comparable to the typical lesion size of morphea,which allows for treatment only at the target area. We deploy a compactarray of LEDs to achieve a uniform and tunable irradiance, depending onthe driving current. The use of bioresorbablepoly-lactic-co-glycolic-acid (PLGA) microneedles (MNs) was inspired bythe recent progress on microneedle based transdermal drug delivery.⁶Instead of being a transferring media for drugs, the PLGA MNs are highlytransparent in the UVA region (transmittance >98%) with a refractiveindex similar to those of epidermis and dermis, acting as a light guideto distribute more light into deeper skin. As suggested by Monte Carlosimulation, compared to the standard care, the new device with MN lightguides is expected to deliver 4 times more dosage to deep tissues from500 μm to 1 mm. The UVA-1 dosage on both superficial, shallow skinlayers as well as deep tissues would significantly enhance thetherapeutic efficacy on morphea and other localized sclerodermadiseases. In addition, the integrated device combining the LED lightsource as well as the bioresorbable light engineering unit in a flexibleform is a versatile platform for a broad range of light therapy andphotomedicine related applications.

FIG. 1A shows an exploded scheme of the integrated device containing twofunctional units: i) a 3 by 3 array of light sources (UVA-1 LEDs) andii) the bioresorbable PLGA MNs as light guide (e.g., microarray oftissue penetrating members). The LEDs are assembled on a polyimidesubstrate (75 μm thick) with 18 μm-thick copper circuits andencapsulated with an encapsulation layer (such as a thin layer ofpolydimethylsiloxane (PDMS, <10 μm)) for electrical insulation. UncuredPDMS was also used as the adhesive to bond the LED array and PLGA MNs.The refractive indices for PDMS encapsulation/adhesive layer and PLGAare about 1.43 and 1.45, respectively.⁷⁻⁸ Such an index-matching resultsin negligible reflection loss when UVA light from the LED patchtransmits into the PLGA MNs. FIGS. 1B and 1C show the photographs of theintegrated device, which connects to custom-printed circuit board as aninterface via ACF flexible cable to power source. Moreover, PLGA ishighly UV transparent (measured transmittance >98% in the UVA wavelengthrange).

Recent progress on the integration of light-emitting devices withbiological systems has been translated into clinical technologies suchas sensing⁹ and optogenetics.¹⁰⁻¹¹ Two optical parameters are crucialfor the efficacy of light therapy, light intensity (irradiance) and theuniformity. In the standard care of morphea treatment, the mercury UVAlamp provides a uniform output with a typical light intensity of about20 mW/cm² (can be as high as 80 mW/cm²,¹² depending on the treatmentstrategy). In the newly designed LED array, each LED has an area of 1.6mm by 1.6 mm and a thickness of 1.0 mm (FIG. 2A). The minimal spacingbetween adjacent LEDs (˜0.15 mm), together with the radiant pattern,leads to homogeneous light intensity distribution at −1 mm above the topsurface of the LED patch (FIG. 2C). The uniform light irradiation wasconfirmed by imaging the fluorescence of a commercial fluorophore(Dylight 350) dispersed in 4 wt. % Agarose gel. This fluorophorefeatures with the emission between 400 and 500 nm under UVA-1irradiation. Instead of directly imaging the UVA-1 light (challengingfor most regular optical microscopes), by analyzing the fluorescenceintensity in the visible light regime, one can extrapolate the intensitydistribution of the excitation UVA-1 light (FIG. 2C). Within the LEDarray area (indicated by the dashed boxes in FIG. 2C), we analyzed thefluorescent intensity distribution along 9 randomly distributed linesand found the intensity remained largely unchanged (FIG. 2D). The highlyuniform light intensity can reduce the chance of high intensity “hotspots”, as potential risk for skin cancers, during the treatment. On theother hand, the light dose (radiant energy per area) and irradiance(radiant power per area) are important parameters for practical lighttherapy and photomedicine. A decent irradiance (e.g., 20 mW/cm²) isimperative to deliver adequate dosage within a reasonable amount oftime. The high wall plug efficiency (˜20%, defined as the percentage ofLED converting electrical power into radiant power) of the UVA-1 LEDresults in light intensity (>20 mW/cm²) at a direct current as low as 20mA. When outputting light intensity below 40 mW/cm², the LED array onlyinduces a tolerable temperature increase (lower than 10 C, measured by aFLIR infrared camera).

We deployed a bioresorbable copolymer, PLGA, in the preparation of MNlight guide. PLGA is highly UV transparent. Thus we assume there isnegligible light loss when UVA light propagates in the PLGA needles. Therefractive index of PLGA (1.46)⁷ is similar to those of epidermis(˜1.49) and dermis (˜1.40)¹³⁻¹⁴, which dictates the light dissipation atthe interface (see Monte Carlo simulation). Following a melt moldingmethod in previous reports⁶, we made high needle density PLGA MN arrayswith several configurations. As shown in FIG. 3A, the pyramidal needleshave 1 mm length and various combinations of base size (μm) and spacingbetween the edges of adjacent needles (μm). From left to right, the basesize/spacing of the four arrays are 200/100, 400/200, 300/100, and400/200, respectively. Such close packing translates to high occupancy(defined by the area of the base of needles divided by the area of thewhole MN array) of 44%, 44%, 56%, and 64%, respectively. A highoccupancy of MNs would allow more UVA-1 light delivered to deep skin ifthe needles can easily penetrate the skin. The high Young's modulus (1.4GPa)⁶ of PLGA and the sharp tips of the MNs (10-20 μm) allows for anefficient insertion into pig skin (as an alternative to human skin, theYoung's modulus of skin is in the order of 100 kPa)¹⁵, as visualized bythe stained skin punctured by 1 mm long MNs (FIG. 3B,base/spacing=400/200 μm). The insertion depth is quantified by MRIimaging a PLGA MN array inserted in pig skin and sandwiched with anotherpiece of skin (FIG. 3C). Due to the difference in water content/moistureof the MNs and the skin, the outlines of the inserted MNs were obviousfrom a cross-sectional view (FIG. 3C). The statistical analysis of theinsertion depth of 10 selected needles showed an average insertion depthof 0.74±0.04 mm, which corresponds to ˜75% of the length of needles. Inaddition to the listed configurations, conical MN arrays with needlelengths from 500 μm to 2 mm and occupancy as high as 44% can also bemade using corresponding PDMS molds.

The key of the proposed integrated device for UVA-1 therapy is theenhanced delivery in deep skin via the tissue penetrating members(including microneedles or MN) light guide. To prove this concept, weperformed both optical measurements and Monte Carlo simulation. Agelatin-based phantom with several additives (e.g., intralipid) wasprepared to simulate the optical properties of skin.¹⁶ A collimated 400nm-light source was used to evaluate the light transport in skinmimicking phantom. In the scenario with PLGA MN light guides, there isan obvious increase in the light transport distance (FIGS. 4A-4B). Toquantify the UVA-1 light dissipation in human skin with epidermis anddermis layers, we performed Monte Carlo simulation. This technique hasproven the capability to estimate radiation dosages, such as light, incomplex media where photons are subject to absorption as well asmultiple scattering events.¹⁷ As shown in FIGS. 5A-5F, the introductionof microneedles redistributes the light intensity and allows higherirradiance in deep skin, regardless of the illumination conditions:without divergence (i.e., incident angle=0 degree) or and sweeping withdivergence (from divergence angle of ±45 degree). Beside the local lightintensity distribution around each needle and an array, we can alsoobtain several other important information, including 1) irradiance (inmW/cm²) applied to skin at various depths; 2) dosage (in mW) deliveredto skin at different depth intervals. FIG. 6 compares the irradiance atvarious depths in skin by standard care without MNs and the protocolwith MNs (length=1 mm, base=400 μm, spacing=200 μm). The introduction ofMNs leads to similar irradiance to the standard care in epidermis andslightly higher irradiance in dermis from 100 to 300 μm. Higherirradiance is expected in thicken dermis, especially below 500 μm.Clinically, morphea (localized scleroderma) has been shown to be aslarge as 2.6 mm in thickness (SC/E/Dermis) compared to 1.3 mm inthickness (SC/E/Dermis) of unaffected skin.³ Therefore the enhancedlight irradiance in thicken dermis would benefit the therapeuticresponse. Table 1 compares the dosage delivered at various depthintervals in skin by standard care and the protocols with microneedles.The total power is 9.8 mW. In the standard UVA-1 treatment, most of thelight dose (˜60%) is applied to the top 300 μm thick skin, while lessthan 10% energy can reach to thicken skin below 500 μm. Considering thetypical thickness of morphea, most of the thicken dermis remained mostlyuntreated. In comparison, ˜80% and ˜40% (i.e., 4 times compared tostandard care) of the light dose can be delivered to dermis layer (below100 μm) and thicken skin below 500 μm, respectively, with the assistanceof MNs.

TABLE 1 Dosage power (in mW) delivered at various depth intervals in theskin. The highlighted rows correspond to dose in epidermis and the topdermis. Depth Standard UVA-1 with MNs UVA-1 with MNs intervals UVA-1 (0deg.) (±45 deg.) [μm] [mW] [mW] [mW]  0-200 4.91 2.79 3.59 200-300 2.331.70 1.73 300-400 1.26 1.29 1.35 400-500 0.66 1.00 1.06 500-600 0.320.77 0.75 600-700 0.16 0.66 0.55 700-800 0.08 0.54 0.38 800-900 0.040.45 0.27  900-1000 0.02 0.37 0.18 1000-1100 0 0.26 0.12 1100-1200 00.15 0.06 1200-1300 0 0.07 0.03 1300-1400 0 0.04 0.02 1400-1500 0 0.020.01

Finally, in view of the curvilinear nature of human skin, a flexiblelight therapy device is preferred, especially when treating morphealesions in regions with high curvature such as elbows or joints. The LEDpatch on a 12.5 μm-thick polyimide substrate conforms to the curvatureof a human finger without sacrificing the electrical/optical performance(FIG. 7A). Chemical modification of the handling layer of PLGA MN arrayleads to rigid MNs on a highly flexible handling layer (FIG. 7B). Thebendability of PLGA MN arrays is high enough to accommodate mostcurvatures or surface roughness on human skin. FIGS. 7C and 7D show anoperational, integrated flexible device applied to the arm of a humansubject.

In conclusion, we provide a flexible, wearable integrated light therapydevice utilizing dense microneedle arrays as a light guide to facilitatelight delivery into deep skin. This provides a promising solution totreating skin disease such as morphea. Moreover, this technology couldserve as a versatile platform for various light therapy, with differentwavelength, light intensity, penetration depth, etc.

Fabrication of UVA-1 LED patch. The UVA LEDs with commercial packing(peak emission at 360 nm, VLMU1610-365-135) were purchased from Digikey.The flexible electronic circuit was defined by LPKF Contac S4 fromDuPont Pyralus AP8535R (18 μm copper/75 μm polyimide/18 μm copper). TheLEDs were mounted by low temperature solder (IndiumCorp). The LED patchwas encapsulated with a thin layer of PDMS (DOW corning Sylgard 184,part A: part B=10:1). The device was powered by a precise direct currentsource meter (Keithley 6220, USA). Under a voltage compliance (5 V), aconstant current was applied to achieve a desirable optical radiantpower. The connection between the LED patch and the source meter wasthrough a flexible ACF cable to a custom printed circuit board as aninterface. The radiant power was measured by using a commercial UVAlight meter (SPER Scientific 850009). The UVA light meter was calibratedwith a UVA lamp with known light intensity. The temperature increaseduring the operation of LEDs was monitored by an IR camera.

Preparation of PLGA microneedles. Poly(D,L-lactide-co-glycolide) (PLGA,430471-5g) was purchased from Sigma-Aldrich. We used laser-ablated moldsmade from PDMS (purchased from BlueAcre Technology, Ireland) with thenegative patterns of the microneedles. PLGA pellets were placed in themold and heated at 200° C. for 1 h in a vacuum oven (−25 mmHg). Undervacuum, the molten PLGA filled the cavities of PDMS molds. After cooledto room temperature, a couple of PLGA pellets were added to fill theuncovered area of the mold, followed by heated at 200° C. for 1 h undervacuum. After several cycles, the mold fully filled with molten PLGA wascooled in a refrigerator (−20° C.) for 30 min. The solidified PLGA arraywas then carefully separated from the mold. To make PLGA MNs with ahighly flexible handling layer, prior to the separation between MNs andPDMS mold, several drops of ethyl acetate or acetone were carefullycasted on the handling layer, followed by solvent evaporation in thefume hood. After several drop-cast/solvent evaporation cycles, thehandling layer became high flexible while the needles remained rigid.

Characterization techniques. The microscopic images of Dylight 350containing Agarose gel (1 pg of dye in 3 g of 4 wt. % Agarose gel)placed on top of the UVA-1 LED patch were taken on a Leica DM6BWidefield Fluorescent Microscope. The light intensity distribution ofUVA LEDs was extrapolated by analyzing the fluorescence of Dylight 450.To visualize the light transport distance, gelatin-based phantom wasprepared according to previous reports¹⁶ to simulate the opticalproperties of skin. The insertion of MNs was visualized on Trypan blue(T8154, Sigma-Aldrich) stained pig skin after punctured by MNs. MRI wasperformed on a 9.4T Bruker Biospec MRI system with a 30 cm bore, a 12 cmgradient insert, and an Autopac automated sample positioning system(Bruker Biospin Inc., Billerica, Mass.).

Monte Carlo simulation. We performed Monte Carlo simulation to evaluatethe light dosage in the skin; especially the dermis. The simulationconsists of a light source (20 mW/cm²) impinging on the skin in thepresence of the microneedle array under two illumination conditions:without divergence (i.e., incident angle=0 degree) and with divergence(divergence angle of ±45 degree); and in the absence of the microneedlesas a comparative frame. As described above, the closely packed UVA LEDpatch likely emits light with very narrow incident angles (<5 deg.).Nonetheless, we simulate both cases for better comparison. The totalpower coming from the LED patch is P_(Total)=I_(T)*A_(T)=9.8 mW, whereI_(T)=20 mW/cm², A_(T) is the area with microneedles (7 mm by 7 mm).Power per microneedle (MN) unit cell can be calculated asP_(MN)=I_(T)*A_(T)/n_(Tip), where A_(MN) is the area of the MN unit celland also contains the spacing (d) and n_(MN) is the number of unitcells. To simulate the optical properties of different skin layers, weadopt the absorption and scattering coefficients and the anisotropyfactor from previous reports for the UVA wavelength band and assume a100 μm epidermis layer on top of the dermis. The simulations wereperformed on a single unit cell. From that unit cell the total power andpower outside the needle (the actual power introduced to the skin) werecalculated. Then, the total contribution (power intensity or dosage inthe skin) was calculated by adding (i) the power outside in each needleunit cell multiplying to the total number of MNs in the array and (ii)the power in the gaps between the needle unit cells (data obtained fromthe standard care cases where there are no microneedles). Based on thesimulations, we can obtain several important information comparing thestandard care and the proposed protocol with microneedle arrays,including 1) irradiance (in mW/cm²) applied to skin at various depths;2) dosage (in mW) delivered to skin at different depth intervals; 3)local light intensity distribution around each needle and a needlearray. For all cases, we compared the standard care with the microneedleapproach (collimated irradiation or ±45 deg. divergence).

REFERENCES (FOR EXAMPLE 1)

-   1. Dougherty, T. J.; Gomer, C. J.; Henderson, B. W.; Jori, G.;    Kessel, D.; Korbelik, M.; Moan, J.; Peng, Q., Photodynamic    Therapy. J. Nat. Cancer Inst. 1998, 90, 889-905.-   2. Group, A. A. o. D. W.; Menter, A.; N. J., K.; Elmets, C. A.;    Feldman, S. R.; Gelfand, J. M.; Gordon, K. B.; Gottlieb, A.; Koo, J.    Y.; Lebwohl, M.; Leonardi, C. L.; Lim, H. W.; Van Voorhees, A. S.;    Beutner, K. R.; Ryan, C.; Bhushan, R., Guidelines of Care for the    Management of Psoriasis and Psoriatic Arthritis: Section 6.    Guidelines of Care for the treatment of Psoriasis and Psoriatic    Arthrits: Case-Based Presentations and Evidence-Based    Conclusions. J. Am. Acad. Dermatol. 2011, 65, 137-174.-   3. Serup, J., Localized Scleroderma (Morphoea): Thickness of    Sclerotic Plaques as Measured by 15 MHz Pulsed Ultrasound. Acta.    Derm. Venereol. 1984, 64, 214-219.-   4. Wong, T.; Hsu, L.; Liao, W., Phototherapy in Psoriasis: A Review    of Mechanisms of Action. J. Cutan. Med. Surg. 2013, 17 (1), 6-12.-   5. Meinhardt, M.; Krebs, R.; Anders, A., Wavelength-Dependent    Penetration Depths of Ultraviolet Radiation in Human Skin. J.    Biomed. Opt. 2008, 13, 044030.-   6. Park, J. H.; Allen, M. G.; Prausnitz, M. R., Biodegradable    Polymer Microneedles: Fabrication, Mechanics and Transdermal Drug    Delivery. J. Control. Release 2005, 104, 51-66.-   7. Butler, S. M.; Tracy, M. A., Adsorption of Serum Albumin to Thin    Films of Poly(lactide-co-glycolide). J. Control. Release 1999, 58,    335-347.-   8. Raman, K.; Srinivasa Murthy, T. R.; Hegde, G. M., Fabrication of    Refractive Index Tunable Polydimethylsiloxane Photonic Crystal for    Biosensor Application. Phys. Procedia 2011, 19, 146-151.-   9. Kim, D.-H.; Lu, N.; Ghaffari, R.; Kim, Y.-S.; Lee, S. P.; Xu, L.;    Wu, J.; Kim, R.-H.; Song, J.; Liu, Z.; Viventi, J.; de Graff, B.;    Elolampi, B.; Mansour, M.; Slepian, M. J.; Hwang, S.; Moss, J. D.;    Won, S.-M.; Huang, Y.; Litt, B.; Rogers, J. A., Materials for    Multifunctional Balloon Catheters with Capabilities in Cardiac    Electrophysiological Mapping and Ablation Therapy. Nat. Mater. 2011,    1, 316-323.-   10. II Park, S.; Brenner, D. S.; Shin, G.; Morgan, C. D.; Copits, B.    A.; Chung, H. U.; Pullen, M. Y.; Noh, K. N.; Davidson, S.; Oh, S.    J.; Yoon, J.; Jang, K. I.; Samineni, V. K.; Norman, M.;    Grajales-Reyes, J. G.; Vogt, S. K.; Sundaram, S. S.; Wilson, K. M.;    Ha, J. S.; Xu, R. X.; Pan, T. S.; Kim, T. I.; Huang, Y. G.;    Montana, M. C.; Golden, J. P.; Bruchas, M. R.; Gereau, R. W.;    Rogers, J. A., Soft, Stretchable, Fully Implantable Miniaturized    Optoelectronic Systems for Wireless Optogenetics. Nat. Biotechnol.    2015, 33, 1280-1286.-   11. McCall, J. G.; Kim, T.-i.; Shin, G.; Huang, X.; Jung, Y. H.;    Al-Hasani, R.; Omenetto, F. G.; Bruchas, M. R.; Rogers, J. A.,    Fabrication and Application of Flexible, Multimodal Light-Emitting    Devices for Wireless Optogenetics. Nat. Protoc. 2013, 8, 2413-2428.-   12. Hassani, J.; Feldman, S. R., Phototherapy in Scleroderma.    Dermatol. Ther. (Heidelb) 2016, 6, 519-553.-   13. Meglinski, I. V.; Matcher, S. J., Quantitative Assessment of    Skin Layers Absorption and Skin Reflectance Spectra Simulation in    the Visible and Near-Infrared Spectral Regions. Physiological    Measurement 2002, 23, 741-753.-   14. Salomatina, E.; Jiang, B.; Novak, J.; Yaroslaysky, A. N.,    Optical Properties of Normal and Cancerous Human Skin in the Visible    and Near Infrared Spectral Range. J. Biomed. Opt. 2006, 11, 064026.-   15. Liu, Y.; Pharr, M.; Salvatore, G. A., Lab-on-Skin: A Review of    Flexible and Stretchable Electronics for Wearable Health Monitoring.    ACS Nano 2017, 11, 9614.-   16. Chen, A. I.; Balter, M. L.; Chen, M. I.; Gross, D.; Alam, S. K.;    Maguire, T. J.; Yarmush, M. L., Multilayered Tissue Mimicking Skin    and Vessel Phantoms with Tunable Mechanical, Optical, and Acoustic    Properties. Med. Phys. 2016, 43, 3117-3131.-   17. Glinec, Y.; Faure, J.; Malkaa, V.; Fuchs, T.; Szymanowski, T.;    Oelfke, U., Radiotherapy with Laser-Plasma Accelerators: Monte Carlo    Simulation of Dose Deposited by an Experimental Quasimonoenergetic    Electron Beam. Med. Phys. 2006, 33, 155-162.

Example 2: Phototherapy

Narrow-band ultraviolet-B radiation (NBUVB) phototherapy is effective,safe even for pregnant women and children, and affordable for psoriasis.However, NBUVB takes a long time to work (˜3 months), is inconvenient,does not clear skin as well as newer injectable drugs, and onlypenetrates very shallowly. We propose a new ‘patch-like’ NBUVBtechnology. The device's top layer has micro-light-emitting diodes thatemit NBUVB embedded within soft, flexible silicone that wraps aroundpsoriasis lesions on curvy body surfaces. The second layer, attached tothe skin, includes a microneedle patch with tiny needles (length: 100μm) designed to guide NBUVB deeper into the psoriasis lesion. We thinkthat tighter wrapping and depth enhancement will improve the speed andeffectiveness of NBUVB. We have already shown that we can make a deviceto deliver a different type of light. The three goals of this exampleare to modify the system to deliver NBUVB with shorter microneedles. Thesecond is to show the system works on the benchtop. The third is to showthe device is safe and works in patients with psoriasis. The device isconfigured to be available for home-use that can be ‘cut’ to size totreat any psoriatic lesion.

Phototherapy is the standard of care for several moderate-to-severeimmune-mediated skin disorders, among them psoriasis (inflammatoryscaling disorder), vitiligo (pigmentary loss), and morphea (localizedscleroderma). Topical anti-inflammatory medications—especially topicalcorticosteroids—have remained the treatment of choice for mostimmune-mediated skin disorders of milder severity or more localizeddisease for decades. However, these topical therapies often have limitedefficacy, and patients adhere poorly to treatment regimens because ofconcerns about side effects and inconvenience. In severe cases,immunosuppressive agents can be effective but are costly, particularlyin the case of biologics, and have systemic side effects. Thus,augmented forms of phototherapy that is more efficacious, faster indelivering therapeutic response, affordable, and suitable for home usewould offer a significant therapeutic advance.

UVB (290-320 nm) and more specifically narrow-band ultraviolet light(NBUVB, 311 nm) have shown excellent efficacy for psoriasis on a parwith injectable biologics therapy. Phototherapy has no systemic sideeffects such as immunosuppression, and is safe to use in pregnantwomen.¹ In psoriasis, NBUVB reverses the pro-inflammatory cytokineprofile by shifting the immune response towards the Th2 axis and awayfrom the Th1/Th17 axis that drives the disease; another key mechanisminvolves NBUVB's induction of apoptosis and depletion of T lymphocytesin psoriasis lesions.² Meta-analyses demonstrate that 75% of psoriasispatients have at least a 75% reduction in the Psoriasis Area andSeverity Index (PASI) after 4-6 weeks of NBUVB treatment, makingphototherapy one of the most efficacious therapies.³ The annual economicdisease burden is up to $35.2 billion USDs⁴ with a prevalence of 3%among U.S. adults.⁵ The psoriasis disease burden, coupled with theestablished efficacy of NBUVB phototherapy makes psoriasis an ideal testplatform.

UVA1 (340-400 nm) has shown distinct biological effects from UVB. Giventhe longer wavelength, UVA1 penetrates deeper into tissue (dermis andsuperficial fat), delivering therapeutic benefit in sclerotic skindiseases with limited therapeutic options, such as morphea, systemicsclerosis and lichen sclerosis.⁶ Phototherapy's therapeutic effect hasbeen attributed to: i) reducing fibroblast expression of TGF-β, a keygrowth factor in propagating fibrosis; ii) increasing collagenase mRNAexpression 20-fold; iii) causing apoptosis of infiltrating T-cells; andiv) inducing neo-vascularization.^(6,7,8)

Existing NBUVB and UVA1 Phototherapy Systems: NBUVB is traditionallydelivered via mercury gas lamps (Philips TL01) with spectral filtersthat are inherently inefficient and require high-energy input. Inaddition, these mercury gas lamps have limited shelf lives, requiringfrequent replacement because of decreased performance with time.Furthermore, traditional NBUVB systems are limited in their ability tobe selective in regards to treatment area. Thus, energy is delivered toboth target psoriatic lesions and normal skin and, because of the lowertolerance to UVB radiation of normal skin (erythema and pain), must beslowly over weeks before a therapeutic dose is delivered to thepsoriatic lesion.⁹ NBUVB is typically first given to a patient in aphysician's office to assess tolerance and skin response. Patients cometo the office 2-3 times a week for therapy, leading to an untenableburden of both cost and inconvenience in comparison to other availabletreatment options.¹⁰ Although home phototherapy units are effective, fewpatients are able to utilize home therapy; both insurance coverageissues and patient safety concerns dictate the need for a several monthperiod of physician office-based phototherapy before home phototherapyunits become an option.¹¹ The xenon-chloride excimer laser is able todeliver targeted NBUVB therapy to a smaller surface area.¹² With theadvantage of higher energy delivery to only lesional skin, the excimerlaser still exhibits significant limitations. The device is highlyexpensive, poses an ophthalmic risk, and not suitable for home use.Although UVA1 causes significantly less skin erythema compared to NBUVBand thus enables the delivery of more energy, UVA1 to unaffected skinleads to skin hyperpigmentation, premature photoaging, and an increasedrisk of cutaneous malignancy.¹³ To avoid this, patients must put onlayers of protective clothing. This can be uncomfortable, given thelength of time necessary for UVA1 phototherapy (>15 minutes per session)and the heat generated by the systems. Finally, UVA1 remains challengingto obtain, given that few providers offer UVA1 phototherapy. Both UVA1and NBUVB require titration of the light dose to accommodate skintolerance. Since the wavelengths for UVA1 and NBUVB are relativelyshort, there is limited skin penetration, which precludes the ability totreat skin lesions more than 1 mm thick.

The development of aluminum gallium nitride and aluminum nitridematerials has enabled the fabrication of light emitting diodes (LEDs)with emission wavelengths less than 400 nm,¹⁴⁻¹⁵ which are commerciallyavailable. There are several advantages to the use of LEDs for UVB andUVA light delivery. First, LEDs exhibit significantly higher shelf lifeand robust performance over time, compared to gas lamp systems. Second,LEDs are much more affordable to manufacture than excimer laser systems.Third, LEDs can be specifically constructed to emit a narrow spectralband (e.g. 311 nm), negating the need for extraneous filters, which leadto heat generation and energy inefficiency. Lastly, LEDs can operateusing direct current, enabling battery power for operation with nocool-down or warm-up necessary. Previous studies have demonstrated thepreliminary clinical efficacy of NBUVB therapy with LEDs using aprototype device⁹; there are existing FDA-cleared LED phototherapydevices (e.g. Psoria-Shield™) approved for the treatment of psoriasis.However, new LED phototherapy devices simply recapitulate gas lampsystems without significant improvements in device wearability, patientconvenience, and phototherapy efficacy. Currently, there is a need formore effective, more convenient, and wearable home UVB and UVAphototherapy systems. Innovation in this field will deliver significantpatient benefit by augmenting the efficacy of phototherapy for a rangeof dermatological conditions.

Definitions of Optical Parameters: Irradiance (mW/cm²): radiant energyflux per unit area. In assuming light is considered a therapeutic class,irradiance would effectively represent the ‘medicine’. Radiant Exposure(mJ/cm²): irradiance of a surface integrated over time of irradiation orsimply the radiant exposure received by a surface per unit area. Inassuming light is considered a therapeutic class, radiant exposure wouldeffectively represent the ‘dose’. Pulse configuration: describes thepulse characteristics of the light energy being delivered. This canrepresent either high intensity short pulses or low intensity sustainedpulses. Dose time: relates to the time necessary to deliver a specificradiant exposure for a given irradiance.

Advantages of Flexible Electronics: The development of curvilinear,hyper-flexible epidermal electronics using inorganic semiconductormaterials was pioneered by the Rogers group.¹⁶ Through photolithographicpatterning and chemical etching techniques, silicon ribbons andmembranes with thicknesses in the nanoscale range can be created from asource silicon wafer. Through transfer printing, these nanoribbons andnanomembranes can be deployed on an elastomer such as(poly)dimethylsiloxane (PDMS) from their source wafer.¹⁷ The ability tocreate bendable connections enables the development of novel flexibledevices. Low profile silicon metal oxide semiconductor field-effecttransistors (MOSFETs) can be deployed within the PDMS substrate andconnected with nanoribbons to create devices of a myriad of functions.The relationship between the mechanics of the silicon ribbons andperformance has been tested extensively in the lab. Serpentine ribbonconfigurations enable strain of up to 30% or more without deteriorationin performance.¹⁸ There is demonstrated robustness and high-performanceof those devices in measuring a wide range of clinically usefulparameters, including but not limited to: temperature, blood flow,stretch, ambient UVA and UVB exposure, EKG, EEG, and EMG.¹⁹ Given theuse of inorganic semiconductor materials and standard manufacturingtechniques, flexible electronics offer both novel functions as well as ahighly favorable cost profile.

Novel LED technologies (FIG. 9) have been developed, including inorganicμLEDs in flexible substrates.²⁰ The μLEDS can be created with a widerange of dimensions from as large as 1×1 mm² to as small as 25×25 μm.²The flexible μLEDs are fabricated using transfer printing on a flexiblePDMS substrate. The thermal dissipation properties of μLEDs placedwithin flexible substrates have also been characterized within the lab.Through both experimental and theoretical monitoring techniques,²¹ heatflow within these structures has shown passive cooling through directthermal transport of flexible metallic wires. Alterations of LED densityand geometric configurations can be optimized depending on the necessaryirradiance of the LED and desired radiant exposure.

Novel Use of Microneedles as Optical Waveguides: Increasing CutaneousPenetration Depth

The optical power of an incident light at 311 nm (NBUVB) and 340 nm(shorter end of UVA1) is limited to 60 μm and 100 μm, respectively,²²translating into limited penetration into the epidermis (NBUVB) andupper reticular dermis (UVA1). Sclerotic diseases such as morphea affectthe entire dermis and subcutis, which are millimeters deep. There is anopportunity to tune penetration for thicker skin lesions or inapplications that extend to the subcuticular tissue.

Research in flat planar microneedles has largely focused on the use ofthese tools for vaccine and drug delivery. In dermatology, microneedleshave also been studied as aesthetic devices for treating facial wrinklesand acne scarring. As FDA-registered low-risk Class I medical devices,these are available for consumer purchase without a physician'sprescription or supervision.²³ These devices involve rolling smallneedles of set length (0.5 mm to 4 mm) repeatedly over the skintreatment area to create painless micro-punctures that augment theefficacy of topical drugs. Microneedles may serve another purpose asuseful conduits to enhance light delivery to the skin (“waveguides”).While implantable polymers have been developed to guide light, thesedevices require a surgical procedure to implant and are limited to thedelivery of longer wavelength (visible light).²⁴

Provided herein is a new medical device to deliver UV phototherapycapable of targeting deeper tissue depths. Through initial benchvalidation and optical simulations, a flexible microneedle light therapysystem directly adhered to the skin provides advantages over existingclinical-standard phototherapy systems. To address the issue of lightpenetration, we provide coupling of a microneedle waveguides opticallyengineered to deliver short-wavelength light (UVB and UVA) with aflexible substrate embedded with UV LEDs, to enhance therapeutic effect.

Phototherapy is as efficacious as TNF-α inhibitor therapy and has anexcellent safety profile (including as first-line therapy in pregnantwomen with psoriasis).²⁵ However, the utilization of light therapy hasdeclined in popularity in comparison to biologics therapy²⁶ due to thedifficulty in obtaining access and the longer time before clinicalefficacy compared with biologics.²⁶⁻²⁸ The development and validation offlexible microneedle light therapy system with optical microneedlewaveguides would represent a new home-based therapeutic paradigm forphototherapy, especially for more localized lesions.

Beyond lower cost and greater convenience, a flexible microneedle lighttherapy device integrated on skin lesions offers the potential forincreased clinical efficacy. This hypothesis is based on severalfundamental physics laws governing light delivery. Traditional NBUVB andUVA1 gas-lamp systems require users to stand within a large booth. Thedistance between the gas-lamps and the user is at least 6 cm. AlthoughLEDs contain a lens (in contrast to the gas lamp systems), experimentalmodels have demonstrated that LED sources still follow a modifiedinverse square law²⁹, meaning that irradiance decreases proportional tothe square of distance when assuming an isotropic radiator. Practically,a light therapy device intimately mated to the skin enables the sametherapeutic effect by reducing surface reflection, and energy loss withdistance.³⁰ The ability to intimately integrate with the skin through aflexible microneedle light therapy system will enable more precise anddirect delivery of light. The reduction in distance between theirradiance source (UV-LED) and the target (psoriasis) by at least oneorder of magnitude will enable increase the effectiveness of theirradiance and/or reduce the power requirements to deliver the sameeffective irradiance to the skin.

For many inflammatory skin lesions and neoplasms, the lesion extendsbeyond the surface of the surrounding skin. For example, thehistopathology of psoriasis is characterized by a thickened stratumcorneum and hyperplasia of the epidermis. Thus, psoriatic lesions extendabove the plan of normal skin. A flexible microneedle light therapydevice has the advantage of allowing for targeted phototherapy acrossthe entire area of the skin lesion, including the portion of the lesionthat extends above the surface of unaffected skin (e.g. the sidewall ofa thicker psoriatic lesion). Existing phototherapy systems only treatlesional skin perpendicular to the orientation of the lamps. Thus, asystem able to deliver UV light along the surface area and height of anyskin lesion (e.g. psoriasis) would enable superior efficacy.

FIG. 10 is a schematic that indicates how the microneedle tips augmentthe delivery therapeutic light for improved clinical efficacy and fasterresponse. Therapeutic UVA1 is disseminated throughout the entire lengthof the microneedles as well as the tip. The ability to direct lightdelivery to various tissue depths provides a therapeutic advantage overexisting systems. The significance of this research extends beyondimproving phototherapy for dermatoses already known to be responsive tophototherapy (e.g. morphea or psoriasis). Skin lesions or growths thatextend below the epidermis and upper dermis susceptible to UV therapywould potentially be treatable with phototherapy opening newopportunities for clinical applications and research.

The tissue penetrating member is compatible with additional opticalcomponents to provide a controlled light intensity profile tosurrounding tissue, including as a function of penetration depth. Forexample, FIG. 42 illustrates an optical component that is a coatinglayer that blocks light, such as a UV blocker. In this manner, lightintensity can vary as a function of penetration depth.

In Silico Experiments to Determine Optimal Microneedle WaveguideGeometries and LED Operation

Using MatLab's (MathWorks, Natick, Mass.) optical simulation toolbox, wehave determined preliminary configurations of microneedles for thedelivery of UVB and UVA1 light. First, we model the behavior of lightwithin skin tissue by plugging in absorption coefficients and scatteringcoefficients of skin, as previously determined.³¹ Simulations enabled usto determine the effect of needle geometry (e.g. tetrahedral, conical).In our preliminary data, we demonstrate the simulated light dissipationof UVA1 across the length of a tetrahedral microneedle. Identifying theoptimal polymer for microneedle composition requires consideration ofoptical transparency (so that the light can get into the surroundingtissue), stiffness (to ensure skin penetration), and biocompatibility.We have identified poly lactic-co-glycolic acid (PLGA) as one targetpolymer, given its excellent optical properties, high stiffness, andexcellent biocompatibility.³² Alternatives include polylactic acid,poly-methyl-methacrylate, and carboxymethyl cellulose. Finally, thedensity of the microneedles are assessed with simulations to determinehow decreasing microneedle pitch (distance between each individualneedles) increases light transmission. As shown below (FIG. 11), thepresence of the microneedles significantly increases UV lightdissipation in skin (compare 1000 μm to 400 μm).

There are several important safety parameters to consider. The UV LEDsare theoretically modeled with respect to heat dissipation when embeddedin various flexible substrates such as PDMS. The encapsulation of thedevice with various flexible substrates affects heat dissipation. Wehave experience with finite element modeling (FEM) of the performance ofLEDs in flexible substrates using commercially available software(ABAQUS).³³ For this example, we model light-current-voltage curves forUV-LEDs of varying sizes. This means that with increasing current inputfrom a battery source, we will know how much heat is created anddissipated. Given the intimate connection with the epidermis,temperature dissipation is a critical consideration. Thus, carefulmodeling will be performed to assess how changes in temperature varywith inputted power. Detailed thermal analyses and modeling have beenperformed previously for LEDs deployed in a flexible configuration andlayout.³⁴ This previous work provides a specific heat transfer modelthat can be deployed for the specific aims in this proposal involvingmultiple arrays of LEDs. In instances where heat generation exceeds 10°C. (threshold of pain in humans), we will vary the geometry of the LEDs.This may include changing parallel arrays into hexagonal arrays within astandard surface area (2 cm×2 cm). Combined with optical andoptoelectronic modeling, we determine the maximum LED density allowablebefore temperature changes degrade performance or represent a risk forthermal injury. Multiple substrates with varying thermal conductivitycharacteristics are tested.

For example, FEM analysis will include PDMS (0.15 W/m/K), glass (1.4W/m/K), benzocyclobutene (0.3 W/m/K), polyethylene terephthalate (0.15W/m/K), and composite silicones. The power requirements will then becalculated depending on the final allowable LED density. The FEManalysis will also analyze component buckling with various levels ofstrain.³⁵ The characterization of the mechanics of the device will allowus to select the ideal elastomer, and ensure device performance whendeployed on human skin. Finally, we have experience in deployingmultiple power options including the use of embedded batteries, nearfield communication (NFC) chips, and Bluetooth.¹⁷ Our design goal is toensure that at least 1 mW/cm² of irradiance is delivered predominatelyin the spectral band between the excimer laser (308 nm) and the PhilipsTL01 mercury gas lamps (311 nm) while ensuring adequate temperaturedissipation. Modeling will ensure the device will operate with thedesired characteristics. Our current preliminary data demonstratesincreased UVA1 delivery which can be further improved with additionalmicroneedle geometries, microneedle density configurations, and LEDdensity configurations to further optimize light delivery for NBUVB andUVA1.

Develop and Characterize Microneedle Designs Optically Engineered forNBUVB and UVA1 Light Delivery

Additional microneedle molds are optically engineered for light deliveryfor UVA1 and NBUVB light. This requires consideration of several factorsincluding biocompatibility, optical transparency, and mechanicalrobustness. Matching epidermis and dermis refractive index enables theoptimal dissipation of UVA1 and NBUVB light based on the FresnelEquation of light loss by reflection. Poly(lactic-co-glycolic acid) orPLGA represents an optimal polymer given its good refractive index matchand high stiffness (2 GPa), which enables epidermal and dermalpenetration. Construction of the microneedle array can be accomplishedwith several strategies. Molds from PDMS can be made from metalmicroneedle masters available off-the-shelf. In our preliminary data, wetook an off the shelf metal mold to create a negative mold. Then, weembedded solubilized PLGA and poured it into this mold. The PLGAmicroneedles are shown here with transmission electron microscopyillustrating the array of microneedles. The length of the needles is 700μm with a pitch distance of 500 μm (space between needles).

Although using microneedle masters is a straightforward constructionmethod, further changes may enable more control over microneedledensity. This includes strategies such as electroplating of metals intodenser microneedle masters. Denser microneedle arrays would furtherincrease UV light delivery. While PLGA is a promising, biocompatiblematerial, other polymers such as poly(vinyl pyrrolidone) PVP orpolylactic acid (PLA) may offer advantages. This includes better opticalmatching to increase UV light dissipation or softer microneedles thatare more comfortable for patients (see, e.g., Table 2).

TABLE 2 Multiple polymers represent potential materials for themicroneedles. Young's Refractive Polymer Modulus Index Polylactic Acid(PLA) 3.5 GPa 1.53 Poly(vinyl pyrrolidone) (PVP) ~1 GPa 1.55Poly(lactic-co-glycolic acid) (PLGA) ~2 GPa 1.46 PDMS <3 MPa 1.40Epidermis 1.47 Dermis 1.40

Histological Testing of Microneedle Performance

Ex vivo testing of microneedle performance on cadaveric porcine skin, anaccepted model for microneedle validation³⁶, can be utilized. Using ourpreliminary molds of PLGA, I applied them to cadaveric porcine skin todemonstrate the successful formation of microneedle channels afterinsertion. Although the needles are 700 μm in length, the microneedlechannels in H&E histology vary from 200-400 μm. This discrepancy islikely fixation artifact. We can utilize longer microneedles and furtherhistological characterization of penetration.

Evaluating Light Dissipation in the Microneedle Waveguides

The evaluation of the PLGA microneedles shows lateral and deep lightdissipation. These experimental data are obtained using agarose gelpenetrated by our PLGA microneedles. Confocal microscopy is used tomeasure the intensity of fluorescence (visible green light) through thelight channels created by the microneedle waveguides. We use visiblegreen light given the ease of visualization. Further experimentationunder will involve testing the dissipation of UV-light and aUV-spectrophotometer (Ocean Optics) within the lab.

Perform Ex Vivo Experiments to Characterize the Optical Performance,Heat Dissipation, and Microneedle Performance for an Integrated UVA1 andNBUVB Flexible Microneedle Waveguide Therapy Patch

We determine optimal existing off-the-shelf LEDs for UVB light delivery:Currently, there are several existing manufacturers that offer LEDs withperformance characteristics that theoretically meet the requirements forNBUVB and UVA1 phototherapy. The criteria include several requirements.The first and foremost is production of light at a narrow spectrum ofactivity (˜311 nm). The second requirement is the ability to deliverenergy at irradiances (1 mW/cm²) that have been previously validated asnecessary to deliver a therapeutic effect.⁹ The third requirement isthat the device can operate in continuous cycle to deliver an effectiveenergy dose of 100 to 500 mJ/cm². The energy dose varies with patientskin type (fairer skin requires less total energy) and is up-titrateddepending on clinical response. For instance, MarkTech Optoelectronics(Albany, N.Y.) offers potential options with LEDs at the 310 nm±5 nmspectrum (FIG. 13). The low profile (4 mm) enables the delivery of up to1 mW/cm² as each LED is capable of generating up to 0.8 mW of power. ForUVA1, there are multiple potential suppliers. Vishay (Shelton, Conn.)offers numerous micro and mm-scale UVA1 LEDs that re-capitulate theoptical parameters of UVA lamps with peak spectral outputs at 360 nm andwith irradiance outputs up to 30 mW/cm².

Testing performance characteristics of off-the-shelf LEDs for UVA andUVB light delivery: Electrical measurements will be performed with asemiconductor parameter analyzer. This will involve measurement ofperformance changes of UV-LEDs with variations in injection current(mA). The operating parameters of the UV-LEDs will be determined withvarying levels of applied current up to the maximum specified by themanufacturer. The optical parameters of the LEDs will be assessed usinga high-resolution spectrometer (HR4000, Ocean Optics). The heatgeneration of each LED will be quantified using mid-wave length infraredthermal imaging (InfraScope, Quantum Focus Instruments). Finally, wewill test that the spectral and energy output of the LEDs maintainstability over time. After demonstrating the optical and powerperformance of available off the shelf UV-LEDs in isolation, we willthen move on to assess optimal geometric arrangements. Using aspectrophotometer, we have confirmed the spectral output of Vishay'sUVA1 LEDs and have selected these off-the-shelf LEDS to pursue furtherdevelopment. We similarly select and validate NBUVB LEDs. In cases wherecommercially available UV LEDs do not meet our needs, we can constructappropriate LEDs.

We embed UV LEDs on a flexible silicone substrate: A procedure forfabricating flexible phototherapy devices are described as follows:

1. A single silicon crystal wafer is coated with a layer of poly(methylmethacrylate) and polyimide.

2. With photolithography (AZ P4620 AZ 400k), the wafer is patterned witha bilayer of copper deposited with an electron beam evaporator (e-beamevaporator, AJA). This technique defines the temperature sensing/heatingelements. A second layer of multilayer of titanium, copper, and gold islithographically patterned to form precise nanometer-thin ribbons andmembranes. A second layer of polyimide provides electrical insulationand mechanical strain isolation.

3. Reactive ion etching defines the mesh layout.

4. Water soluble tape (5414, 3M, US) can be used to remove the layoutfrom the silicon wafer.

5. A soft stamp made of an elastomer such as PDMS or silicone (Ecoflex,Smooth-On, USA)˜5 μm in thickness is designed to allow retrieval of thenanoribbons via transfer printing.

6. Incorporation of UV-LEDs patterned within the substrate will first bedone manually to enable rapid prototyping. A flip-chip method allowsassembly of components interconnected by the nanoribbons.

7. Incorporation of power source either as an integrated coin cellbattery or through a wireless power strategy. The Rogers group has doneextensive work on the power requirements of flexible devices.³⁷ A thinflexible, conductive cable (HST-9805-210, Elform) can be bonded tocontact pads in the device to connect with external electronics such asadditional power sources or data acquisition units.

8. Embed a UV protective covering with incorporation of titanium oxidewithin the outermost layer of the elastomer (PDMS)³⁸ of the device forophthalmologic protection.

9. Adhere base-layer of polymeric microneedle waveguides to theconstructed UV LED device.

The nanoribbons can be patterned in both 2-D and 3-D configurations withhigh throughput. Multiple layers can be added to create more complexdevices. The serpentine design of the nanoribbons has been carefullyelucidated to enable strain that is biomimetic with the epidermiswithout loss of performance. With deformation, the system canstrain-isolate critical components of the device. Furthermore, the aboveprototyping techniques are highly scalable to existing fabricationtechnologies yielding the ability to create flexible light therapysystems at costs low enough to operate as disposable devices. Ourpreliminary work shown below demonstrates the feasibility of patterningan array of 1.6 mm UVA1 LEDs with copper interconnects. This array hasbeen deployed into a flexible PDMS substrate with an adherent layer ofmicroneedle waveguides composed of PLGA. FIG. 9 demonstrates a prototypedevice. Further development will involve increasing LED density toensure adequate light delivery to the surface of the target as well asimproving device flexibility to treat curvilinear surfaces.

Characterization of the physical properties of the UVB-LED epidermal,flexible device in bench testing: Optical performance: Using ahigh-resolution spectrometer (HR4000, Ocean Optics), we will assess thespectral output of the UV LEDs (UVA1 and NBUVB) when embedded within aflexible substrate and adhered to a microneedle waveguide. This isimportant to ensure that the spectral and power output of the entiresystem is safe and effective for human testing. We will assess any edgeeffects and light leakage from the device surface in regards to spectraloutput. UV light poses an ophthalmological risk. Thus, the adequacy ofthe protective outer UV-coating must be tested. Mechanical robustness:Protocols to assess the mechanical robustness of flexible electronicshave been established previously in the Rogers' laboratory.³⁵ The labhas a custom uniaxial/biaxial stretcher for inducing controllabledeformations. A single lens reflex camera captures deformation and adynamic mechanical analyzer (TA instruments, Q800) can yieldstress/strain curves. A DC source-meter (Model 2400, Keithley) willmeasure electrical performance with repeated deformation. Temperaturesafety: Previous works have illustrated that temperatures up to 43° C.is safe in patients for pulse oximeter devices left on for 8 hours orless.³⁹ The thermal transport characteristics of human skin in vivo havealso been previously studied.⁴⁰ Thus, experimental modeling can bedeployed to ensure adequate heat dissipation within the experimentaldesign. The Roger's laboratory has a thermal imager (FIIR E5) device toensure real-world thermal safety.

Trial Evaluating the Performance of the UVA1 Flexible MicroneedleWaveguide Device for the Treatment of Morphea in Adults.: Morphea is alocalized fibrosing skin disease that affects both pediatric and adultpatient populations in equal rates at an incidence of up to 2.7 newcases per 100,000 people per year.⁴¹ There are several clinicalvariants. The appearance of firm, indurated plaques overlying joints orthe face can be disfiguring and cause significant morbidity. Systemictherapy with methotrexate or systemic steroids are not ideal for longterm therapy given the risk of side effects, particularly in the case ofpediatric patients.⁴² Topical therapies are only minimally beneficial.UVA1 has been well studied and shown to be effective without the risk ofsystemic side effects but the lack of availability and patientinconvenience limits its use.⁶ Experimental primary endpoints include avalidated scale (mLoSSI) for morphea and a Physician Global Assessmentof Activity after 15-30 sessions of UVA1 phototherapy.⁴⁴ Durometry, anon-invasive device, will also be to quantify tissue hardness betweenthe experimental device and traditional UVA1 phototherapy at 15 and 30sessions. Finally, histological evaluation of patients graded by adermatopathologist will be conducted after 30 phototherapy sessions todetermine differences in the depth of skin fibrosis between ourexperimental system and standard of care phototherapy.

There are numerous clinical applications that extend beyond NBUVB andUVA1. For example, modifications of the substrates can enable thedeployment of these devices on oral or mucosa surfaces. From aphotobiology standpoint, I can use the skills learned here to pursuefuture, more fundamental work elucidating biological responses of skinin normal and diseased states in response to light delivery of varyingwavelengths, pulse structures, irradiances, and dosing times.

REFERENCES FOR EXAMPLE 2

-   1. American Academy of Dermatology Work, G.; Menter, A.; Korman, N.    J.; Elmets, C. A.; Feldman, S. R.; Gelfand, J. M.; Gordon, K. B.;    Gottlieb, A.; Koo, J. Y.; Lebwohl, M.; Leonardi, C. L.; Lim, H. W.;    Van Voorhees, A. S.; Beutner, K. R.; Ryan, C.; Bhushan, R., Journal    of the American Academy of Dermatology 2011, 65 (1), 137-74.-   2. Wong, T.; Hsu, L.; Liao, W., J Cutan Med Surg 2013, 17 (1), 6-12.-   3. Lapolla, W.; Yentzer, B. A.; Bagel, J.; Halvorson, C. R.;    Feldman, S. R., Journal of the American Academy of Dermatology 2011,    64 (5), 936-49.-   4. Evans, C., Am J Manag Care 2016, 22 (8 Suppl), s238-43.-   5. Rachakonda, T. D.; Schupp, C. W.; Armstrong, A. W., Journal of    the American Academy of Dermatology 2014, 70 (3), 512-6.-   6. Teske, N. M.; Jacobe, H. T., Clin Dermatol 2016, 34 (5), 614-22.-   7. Stege, H.; Berneburg, M.; Humke, S.; Klammer, M.; Grewe, M.;    Grether-Beck, S.; Boedeker, R.; Diepgen, T.; Dierks, K.; Goerz, G.;    Ruzicka, T.; Krutmann, J., Journal of the American Academy of    Dermatology 1997, 36 (6 Pt 1), 938-44.-   8. Zandi, S.; Kalia, S.; Lui, H., Skin Therapy Lett 2012, 17 (1),    1-4.-   9. Kemeny, L.; Csoma, Z.; Bagdi, E.; Banham, A. H.; Krenacs, L.;    Koreck, A., Br J Dermatol 2010, 163 (1), 167-73.-   10. Yeung, H.; Wan, J.; Van Voorhees, A. S.; Callis Duffin, K.;    Krueger, G. G.; Kalb, R. E.; Weisman, J. D.; Sperber, B. R.;    Brod, B. A.; Schleicher, S. M.; Bebo, B. F., Jr.; Shin, D. B.;    Troxel, A. B.; Gelfand, J. M., Journal of the American Academy of    Dermatology 2013, 68 (1), 64-72.-   11. Nolan, B. V.; Yentzer, B. A.; Feldman, S. R., Dermatol Online J    2010, 16 (2), 1.-   12. Passeron, T.; Ortonne, J., Clinics in Dermatology 2006, 24 (1),    33-42.-   13. Vangipuram, R.; Feldman, S. R., Oral Dis 2016, 22 (4), 253-9.-   14. Khan, A.; Balakrishnan, K.; Katona, T., Nature Photonics 2008,    2, 77-84.-   15. Taniyasu, Y.; Kasu, M.; Makimoto, T., Nature Photonics 2006,    441, 325-328.-   16. Rogers, J. A., JAMA 2015, 313 (6), 561-2.-   17. Kim, D. H.; Lu, N.; Ma, R.; Kim, Y. S.; Kim, R. H.; Wang, S.;    Wu, J.; Won, S. M.; Tao, H.; Islam, A.; Yu, K. J.; Kim, T. I.;    Chowdhury, R.; Ying, M.; Xu, L.; Li, M.; Chung, H. J.; Keum, H.;    McCormick, M.; Liu, P.; Zhang, Y. W.; Omenetto, F. G.; Huang, Y.;    Coleman, T.; Rogers, J. A., Science 2011, 333 (6044), 838-43.-   18. Sun, Y.; Choi, W. M.; Jiang, H.; Huang, Y. Y.; Rogers, J. A.,    Nat Nanotechnol 2006, 1 (3), 201-7.-   19. Kim, D. H.; Ghaffari, R.; Lu, N.; Rogers, J. A., Annu Rev Biomed    Eng 2012, 14, 113-28.-   20. Kim, R. H.; Tao, H.; Kim, T. I.; Zhang, Y.; Kim, S.; Panilaitis,    B.; Yang, M.; Kim, D. H.; Jung, Y. H.; Kim, B. H.; Li, Y.; Huang,    Y.; Omenetto, F. G.; Rogers, J. A., Small 2012, 8 (18), 2812-8.-   21. Kim, H.-s.; Brueckner, E.; Song, J.; Li, Y.; Kim, S.; Lu, C.;    Sulkin, J.; Choquette, K.; Huang, Y.; Nuzzo, R. G.; Rogers, J. A.,    PNAS 2011, 108 (25), 10072-10077.-   22. Meinhardt, M.; Krebs, R.; Anders, A.; Heinrich, U.; Tronnier,    H., J Biomed Opt 2008, 13 (4), 044030.-   23. Doddaballapur, S., J Cutan Aesthet Surg 2009, 2 (2), 110-1.-   24. Nizamoglu, S.; Gather, M. C.; Humar, M.; Choi, M.; Kim, S.;    Kim, K. S.; Hahn, S. K.; Scarcelli, G.; Randolph, M.; Redmond, R.    W.; Yun, S. H., Nat Commun 2016, 7, 10374.-   25. Menter, A.; Korman, N. J.; Elmets, C. A.; Feldman, S. R.;    Gelfand, J. M.; Gordon, K. B.; Gottlieb, A.; Koo, J. Y.; Lebwohl,    M.; Lim, H. W.; Van Voorhees, A. S.; Beutner, K. R.; Bhushan, R.,    Journal of the American Academy of Dermatology 2010, 62 (1), 114-35.-   26. Simpson, G. L.; Yelverton, C. B.; Rittenberg, S.; Feldman, S.    R., Journal of Dermatological Treatment 2006, 17 (6), 359-361.-   27. Luersen, K.; Dabade, T.; West, C.; S Davis, S.; Feldman, S. R.,    Journal of Dermatological Treatment 2014, 25 (6), 478-488.-   28. Weng, Q. Y.; Buzney, E.; Joyce, C.; Mostaghimi, A., Journal of    the American Academy of Dermatology 2016, 74 (6), 1256-9.-   29. Karha, P.; Manninen, P.; Hovila, J.; Seppala, L.; Ikonen, E. In    Determination of luminous intensity of light-emitting diodes with    modified inverse-square law., Proceedings of the 9th International    Conference on New Developments and Applications in Optical    Radiometry., Davos, Switzerland, Grobner, J., Ed. Davos,    Switzerland, 2005; pp 211-212.-   30. Li, H., Optik 2014, 125, 1096-1100.-   31. Graaff, R.; Dassel, A. C.; Koelink, M. H.; de Mul, F. F.;    Aarnoudse, J. G.; Zijistra, W. G., Appl Opt 1993, 32 (4), 435-47.-   32. Makadia, H. K.; Siegel, S. J., Polymers (Basel) 2011, 3 (3),    1377-1397.-   33. Kim, T. I.; Lee, S.; Li, Y.; Shi, Y.; Shin, G.; Lee, S.; Huang,    Y.; Rogers, J. A.; Yu, J., Applied Physics Letters 2014, 104,    051901.-   34. Lu, C.; Li, Y.; Song, J.; Kim, H.; Brueckner, E.; Fang, B.;    Hwang, K.-C.; Huang, Y.; Nuzzo, R. G.; Rogers, J. A., Proc. R. Soc.    A 2012, 468, 3215-3223.-   35. Lee, J. W.; Xu, R.; Lee, S.; Jang, K. I.; Yang, Y.; Banks, A.;    Yu, K. J.; Kim, J.; Xu, S.; Ma, S.; Jang, S. W.; Won, P.; Li, Y.;    Kim, B. H.; Choe, J. Y.; Huh, S.; Kwon, Y. H.; Huang, Y.; Paik, U.;    Rogers, J. A., Proc Natl Acad Sci USA 2016, 113 (22), 6131-6.-   36. Chen, Y.; Chen, B. Z.; Wang, Q. L.; Jin, X.; Guo, X. D., J    Control Release 2017.-   37. Kim, J.; Banks, A.; Xie, Z.; Heo, S.; Gutru, P.; Lee, J.; Xu,    S.; Jang, K. I.; Liu, F.; Brown, G.; Choi, J.; Kim, J.; Feng, X.;    Huang, Y.; Paik, U.; Rogers, J. A., Adv. Funct. Mater. 2015, 25,    4761-4767.-   38. Calvo, M. E.; Smirnov, J. C.; Miguez, H., Journal of Polymer    Science Part B: Polymer Physics 2012, 50, 945-956.-   39. Greenhalgh, D. G.; Lawless, M. B.; Chew, B. B.; Crone, W. A.;    Fein, M. E.; Palmieri, T. L., J Burn Care Rehabil 2004, 25 (5),    411-5.-   40. Webb, R. C.; Pielak, R. M.; Bastien, P.; Ayers, J.; Niittynen,    J.; Kurniawan, J.; Manco, M.; Lin, A.; Cho, N. H.; Malyrchuk, V.;    Balooch, G.; Rogers, J. A., PLoS One 2015, 10 (2), e0118131.-   41. Fett, N.; Werth, V. P., Journal of the American Academy of    Dermatology 2011, 64 (2), 217-28; quiz 229-30.-   42. Fett, N.; Werth, V. P., Journal of the American Academy of    Dermatology 2011, 64 (2), 231-42; quiz 243-4.-   43. Christen-Zaech, S.; Hakim, M. D.; Afsar, F. S., Journal of the    American Academy of Dermatology 2008, 59 (3), 385-96.-   44. Kelsey, C. E.; Torok, K. S., Journal of the American Academy of    Dermatology 2013, 69 (2), 214-20.

Example 3: NBUVB

Narrow-band ultraviolet B (NBUVB) phototherapy is an important treatmentmodality for psoriasis¹ that yields a relatively high PASI-75 response(60-75%), lacks potential systemic side effects, and iscost-effective.²⁻⁵ However, NBUVB use in physician offices, which hasbeen primarily for moderate-to-severe psoriasis, has decreased in theU.S. by more than 90% in recent history,⁶ particularly because of thesuccess of biologics.^(7,8) NBUVB is slow, requiring 36 sessions (3months) before meaningful efficacy is seen, and time until response is acritical factor related to patient-reported improvement in quality oflife for psoriasis.^(9,10) Second, newer biologic agents (IL-17 andIL-23 inhibitors) exhibit higher PASI-75 scores compared to NBUVB.¹¹Third, there is a major access barrier, because office-based treatmentsrequire time commitment and travel, may be infeasible for those withmobility issues, and can be costly (each treatment requiring a separateinsurance co-pay).^(12,13) Despite this, phototherapy remains animportant option for psoriasis therapy, especially given its favorablerisk-benefit profile.¹⁴ Furthermore, for patients with mild-to-moderatepsoriasis or limited involvement after systemic intervention, once totwice daily application of topical corticosteroids with or withoutvitamin D3 remains typical therapy is burdensome with high rates ofpatient non-adherence and often incomplete clearance,^(15,16) furtherincreasing the need for new approaches.¹⁰

We provide a novel thin, flexible, and conformable phototherapy devicefor psoriatic lesions, capable of enhancing the depth penetration oftherapeutic NBUVB. The device increases the speed of response andimprove overall efficacy, while remaining cost-effective, safe, andconvenient. The device includes two main components that can operate insynchrony or separately. The outer layer is a thin, flexible array ofmicro-NBUVB light emitting diodes (LEDs) embedded within a flexiblesilicone substrate with circuit interconnects that exactly recapitulatethe optical output of standard-of-care systems. Given its flexibility,it can conform to a psoriatic lesion located on any curvilinear location(e.g. elbow or knee). The inner layer adherent to the skin includes aflexible array of transparent, optically-engineered microneedlewaveguides (PLGA) with a pre-specified depth (100 μm) that can guideincident NBUVB deeper into the psoriatic lesion. This inner microneedlewaveguides can be used separately as an adjuvant for traditionalphototherapy to clear recalcitrant lesions. We propose the followingSpecific Aims:

We have recently developed a flexible, conformable, depth-modulatedphototherapy device that delivers UVA-1 (360 nm) to the skin. Thatsystem is modified to deliver NBUVB with new LEDs capable of a narrowpeak spectral output of 310 nm with lower depth-penetration optimized topenetrate through only the stratum corneum of psoriatic lesions (100μm).

Validate the bench-top performance of the new flexible, depth-modulatedNBUVB phototherapy device for spectral output, mechanical strength, andheat generation in vitro. Success is delivery of 1 mW/cm² of irradiancewith a key spectral output peak at 310 nm.

Safety and efficacy of the NBUVB phototherapy device. We will test thedevice in 3 psoriasis patients starting NBUVB. Physician assessment oferythema, thickness, and scaling of device-treated vs. standardphototherapy will be performed after each NBUVB session up to 36sessions. Success will be parallel efficacy to traditional phototherapyand no evidence of adverse events.

Successful completion will produce preliminary data necessary for futureNIH grant funding for broader, more wide-scale clinical validation.These results will inform future new designs to target special sites(e.g. hands, feet, scalp), where there is a need for improved NBUVBtherapy.

Phototherapy Mechanisms in Psoriasis: NBUVB is thought to reverse thepro-inflammatory cytokine profile in psoriasis by downregulating theTh17 axis,¹⁷ and restoring T_(reg) function by upregulating FOXP3.¹⁸Another key mechanism involves NBUVB's induction of apoptosis ofpathogenic T lymphocytes and keratinocytes.¹⁹ Specifically, activatedT-cells target basal keratinocytes that drive epidermalhyperproliferation.^(20,21,22) Given the known attenuation of NBUVBintensity with depth, specifically in pathologies in which the stratumcorneum is thickened (e.g. psoriasis vulgaris), we hypothesize thatcontrolled, deeper delivery of NBUVB holds significant therapeuticpotential. Clinically, in a double-blind randomized trial, high dose ofNBUVB resulted in more prolonged remission compared to low dose NBUVB.²³In regards to safety, a systematic review of NBUVB did not show anincrease risk of subsequent cutaneous malignancy.²⁴

Limitations of Existing Office and Home-Based Phototherapy Devices:Phototherapy in the office setting is largely delivered via mercury gaslamps (Philips TL01) with spectral filters that are inefficient, haveirregular output across the length of the lamp, require high-energyinput, and have limited shelf life. Patients with moderate to severepsoriasis typically require 36 sessions requiring 3 months of therapybefore meaningful improvement.²⁵ The medical board of the NationalPsoriasis Foundation emphasizes treatment goals that lead to significantskin improvement within 3 months,²⁶ which suggests the need forstrategies that decrease NBUVB response time. Although the excimer laserprovides therapy targeted to localized areas, the system is highlyexpensive, poses an ophthalmic risk, and is not suitable for home use.²⁷While home NBUVB is associated with higher patient satisfaction, andeven cost-effectiveness,²⁸ the use of home NBUVB faces numerousbarriers.^(13,28-30) This includes high initial out-of-pocket expenses¹²in purchasing a home unit, medical-legal risk, and provider concern forthe need for medical supervision.³¹⁻³⁴ Although these barriers persist,continued concerns regarding the cost of biologics^(35,36) and theirunknown long-term safety has increased interest in home NBUVB. NationalBiological® and Daavlin® are established manufacturers offering mercurygas lamp systems (handheld and whole body) for home-use.³⁷ Morerecently, Clarify Medical recently earned FDA-clearance in 2017 for ahandheld LED-based NBUVB system paired to a smartphone.³⁸Psoria-Shield™, though not explicitly marketed as a home-use device, isanother FDA-cleared LED-based NBUVB system.³⁹ While Psoria-Shield™ andClarify Medical offer NBUVB LEDs with greater robustness and no warm-uptime, these systems only recapitulate existing office-based phototherapymodalities without demonstration of increased efficacy or speed untilresponse. Luma™ Therapeutics offers a new approached inspired byGoeckerman therapy by pairing NBUVB with a coal-tar embedded hydrogelpatch.⁴⁰ However, this system requires an additional topical drugcomponent, risks irritant contact dermatitis, may be inconvenient forpatients, and has yet to be validated in larger studies. A phototherapydevice suitable for future home use, designed to do more thanrecapitulate existing systems, would represent a significant advance.

Through advancements in materials science and biomedical engineering, itis now possible to create hyper-flexible epidermal electronics thatresemble temporary tattoos that adhere to any curvilinear bodysurface.⁴¹ Leveraging these advances, a flexible epidermal electronicssystem capable of delivering phototherapy with embedded therapeutic LEDshas the potential to offer more efficacious, faster, and more convenientdelivery. We propose a novel system incorporating NBUVB LEDs in aflexible silicone elastomer coupled to polymeric microneedle waveguidesoptically engineered to allow controlled depth-enhancement of NBUVBdelivery for treating psoriasis. Key advantages include:

Faster Response Time with Enhanced Depth Penetration through MicroneedleWaveguides: The speed to response from NBUVB requires a balance betweenadequate UVB irradiance and radiant energy density per area of skin fortreatment effect without causing deleterious skin erythema. Theadvantages of our technology is that the outermost surface of the skindoes not receive any additional UVB energy compared to traditionalphototherapy systems. However, the microneedles enable delivery oftherapeutic NBUVB to affected T lymphocytes and keratinocytes deeper inthe epidermis than would otherwise not be treated by conventionalsystems. For instance, the average penetration of UVB at 305-320 nm isonly 30 μm.⁴² The stratum corneum thickness of the volar arm is 20 μm,⁴³while the palm and soles averages more than 170 μm.⁴⁴ Moreover,psoriatic lesions are more than 200% thicker than unaffected skin.⁴⁵ Wehypothesize that deeper penetration through the stratum corneum of thickpsoriatic lesions, particularly on acral skin, will enable faster skinclearance. While previous works have developed implantable polymers toguide laser light to deeper tissues, those devices require a surgicalprocedure to implant and have been limited to the delivery of longerwavelengths of visible light.⁴⁶ Although optical clearing agents (e.g.glycerol, perfluordecalin) that reduce light back-scatter and increasetarget transparency have been shown to enhance the efficacy oflaser-assisted tattoo removal (nanosecond QS 755-n Alexandritelaser),^(47,48) these strategies would have minimal effect in enhancingthe absorption of the lower wavelengths in the UV spectra (<400 nm).⁴⁹We propose a conservative microneedle waveguide length of 100 μm topenetrate solely through the stratum corneum (SC) on most glabrous skin.Given the short-length of the microneedles, we expect this to beregulated as a non-significant risk Class II medical device by the FDAenabling direct to human studies. For example, non-sterile dermalmicro-rollers are available without a prescription for cosmetic purposesup to 4,000 μm (4 mm) in length. See FIG. 8.

Greater Efficacy with Conformability to Curvilinear Body Surfaces: Wehypothesize that our ability to wrap circumferentially around apsoriatic lesion will enable improved psoriasis clearance. Thehypothesis is based on several fundamental laws of physics governinglight delivery. Traditional NBUVB systems require users to stand withina large booth or aim a handheld unit at the lesion. The Lambert cosinelaw states that the target irradiance (I_(a)) is equal to the irradiance(I₀) at normal multiplied by the cosine of the angle from normal; thisessentially means that incident UV radiation is most effective when aphoton strikes a surface at 90°. Curvilinear surfaces (e.g. knees)creates ‘cold spots’ for traditional phototherapy systems. Furthermore,peak spectral output of phototherapy lamps is uneven, leaving the lowerlegs and upper body with less energy delivery. Thus, we hypothesize thatintimate integration with the skin through a thin, flexible therapeuticlight system will enable more precise and direct delivery of light (FIG.11).

The device may be ‘cut’ to size by the patient during home use to adesired geometric shape of the psoriatic lesion. Currently, the energyoutput of the system is controlled by the current input from the powersource and time of operation to recapitulate existing energy deliveryalgorithms for NBUVB. Future work can deploy the use of an embeddedBluetooth® control unit in the system enabling smartphone based controlof the NBUVB microneedle waveguides; prior work in our groupdemonstrates the feasibility of this in wearable electronics.⁵⁰

Demonstration of Optical and Theoretical Modeling to Rationally Designthe System: Our preliminary data and studies have shown the feasibilityof a similar system for UVA-1 (360 nm) phototherapy. We first employtheoretical modeling using MatLab's (MathWorks, Natick, Mass.) opticalsimulation toolbox to determine the optimal configuration andcomposition of microneedles for the delivery of UV-light. The absorptioncoefficients and scattering coefficients of skin tissue are used for allsimulations.⁵¹ In our preliminary data, we demonstrate the simulatedlight dissipation of UVA-1 across the length of a tetrahedralmicroneedle (FIG. 11). Minimal modifications to the optical modeling canbe employed to determine NBUVB delivery. Identifying the optimal polymerrequires consideration of optical transparency, stiffness for skinpenetration, and biocompatibility. We have created microneedleprototypes using negative molds of poly lactic-co-glycolic acid (PLGA),given its excellent optical properties and biocompatibility.⁵² Belowshows preliminary data with an image of the microneedles, and TEMcharacterization (FIG. 12). In addition, preliminary tests showmicroneedle channel formation after insertion into cadaveric pigskin.Our preliminary experimental, obtained using agarose gel and confocalmicroscopy, shows increased lateral and deep light dissipation from theoptical channels created by our PLGA microneedles (FIG. 14). Wecalculate that our microneedles increase UV transmittance by 250-300% inthe z-plane along the length of the microneedles. Our UVA-1 prototypedemonstrates the feasibility of an integrated system with a top layer ofUV LEDs (3×3 and 2×2 arrays) within a flexible silicone substrate,adhered to PLGA microneedle waveguides (FIG. 16).

Experiment Design: Develop a NBUVB phototherapy device. Severalmanufacturers offer LEDs with performance characteristics that meet therequirements for NBUVB phototherapy (e.g., MarkTech Optoelectronics(Albany, N.Y.) with LEDs at the 310 nm±5 nm spectrum). The low profile(4 mm) enables light irradiance that is comparable to existing NBUVB gaslamp outputs. To fabricate flexible phototherapy devices: i) a circuitprint layout is constructed with serpentine copper interconnects tofacilitate bending and stretching without breakage; ii) the array ofNBUVB LEDs are added; a flexible, conductive cable is bonded to connectto an external battery; iii) the circuitry is embedded within atransparent silicone elastomer (PDMS, 3M); iv) an optical diffuser isadded to the base and a UV protective covering (titanium oxide) is addedto the top layer⁴¹; and v) the base layer of PLGA polymeric microneedlewaveguides (100 μm), made through a smaller negative mold, is adhered.

Validate the bench-top performance. 1) Optical performance: Using ahigh-resolution UV radiometer (SolarLight), we will assess the spectraloutput (nm) and irradiance (mW/cm²) of the NBUVB LEDs when embeddedwithin a flexible substrate and adhered to the microneedle waveguidesincluding edge leakage, and the adequacy of the protective outerUV-coating. 2) Mechanical robustness: our lab has a customuniaxial/biaxial stretcher for inducing controllable deformations.⁵³ Asingle lens reflex camera captures deformation and a dynamic mechanicalanalyzer (TA instruments, Q800) can yield stress/strain curves. 3)Temperature safety: Temperatures up to 43° C. are safe in patients forpulse oximetry devices worn for ≤8 hours.⁵⁴ Thermal output of the deviceis measured with 1 hour of continuous operation with a thermal camera(FIR E5).

After validation, we will conduct a 3-arm pilot study evaluating thesafety and early efficacy of the experimental system in psoriasispatients (n=3) undergoing NBUVB phototherapy for lesions on glabrousskin. Our goal is to evaluate the safety and early efficacy of theintegrated device with NBUVB LEDs and microneedle waveguides (length 100μm) for psoriatic lesions, and the microneedle waveguides coupled tostandard NBUVB compared with standard NBUVB alone. In the Northwesternphototherapy unit, we will choose patients with two symmetricalpsoriatic lesions at least 9 cm² in size on glabrous skin. Within eachsymmetrical psoriatic lesion, we will identify 2 areas (1 cm² in size)using anatomical landmarks and sequential photography separated by aborder of 2 mm of lesional skin. A medical caliper accurate to 30 μm(Mituyoyo®) will be used to confirm area size. Identify a 1 cm² areawhere a 1 cm×1 cm integrated device with NBUVB LEDs (2×2 array) andmicroneedle waveguides will be placed sequentially. The top layer of theintegrated device blocks all UV from the external environment and thedevice itself. The output of the LEDs will exactly match the settings ofthe standard phototherapy unit at every session. On the contralateralside, identify a 1 cm² area where only the microneedle waveguide patch(1 cm×1 cm) will be placed without a UV-blocking layer. Identify a 1 cm²control area where only standard NBUVB phototherapy is delivered on bothsymmetrical lesions. The integrated device and microneedle waveguidesalone will be applied during each phototherapy session at the samelocation sequentially for 36 sessions.

After every session, the experimental devices are removed and all 4locations will be photographed by a research assistant. Then, the 4locations will be evaluated by 2-blinded dermatologist raters. Each 1cm² site will be scored analogously to the PASI-75 for redness,thickness, and scaling on a 0 (none) to 4 (maximum) scale and aphysician global assessment (0=clear to 4=severe). After 36 sessions,all 4 sites will be biopsied (4 mm punch) and evaluated histologicallyby 2 blinded dermatopathologists to quantify epidermal and SC thickness.A baseline biopsy prior to NBUVB initiation will be taken for comparisonpurposes. The Northwestern's Skin Disease Research Center's Morphologyand Phenotyping Core will perform routine histology and IHC staining forCD3 and KRT16. Adverse effects such as erosions, blistering, ordermatitis (scale 0-3) will be evaluated at every session by both ratersimmediately after device removal and 15 minutes later. In cases wherethe experimental device leads to skin disruption at 15 minutes, it willbe discontinued and the adverse event recorded. We will determinesuccess if the treatment areas evaluated for erythema, thickness, andscaling (0-4) do not exhibit significant differences (one-way ANOVA withpair-wise comparisons) after 36 sessions between the microneedlewaveguides with the coupled NBUVB LED array, traditional NBUVB withaugmentation from the microneedle waveguides, and traditional NBUVBphototherapy alone. If the psoriatic lesion has cleared by raterassessment, NBUVB will be stopped.

Alternative Strategies: Bench testing with our UVA-1 system, whichoperates at a higher current, shows minimal temperature increase atsteady state (<10° C., which is barely noticed). If the heat is toohigh, we can add a thermal insulating layer or increase LED spacing.Although we have identified PLGA as an ideal polymer, we can alsoevaluate other polymers (e.g. poly-lactic acid). The microneedle lengthcan be easily modified by adjusting the mold dimensions. The proposedsystem can treat difficult areas: palms, soles, and the proximal nailfold.

REFERENCES FOR EXAMPLE 3

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UVB phototherapy in an    outpatient setting or at home: a pragmatic randomised single-blind    trial designed to settle the discussion. The PLUTO study. BMC Med    Res Methodol. 2006; 6:39.-   33. Koek M B, Buskens E, Bruijnzeel-Koomen C A, Sigurdsson V. Home    ultraviolet B phototherapy for psoriasis: discrepancy between    literature, guidelines, general opinions and actual use. Results of    a literature review, a web search, and a questionnaire among    dermatologists. Br J Dermatol. 2006; 154(4):701-711.-   34. Yelverton C B, Kulkarni A S, Balkrishnan R, Feldman S R. Home    ultraviolet B phototherapy: a cost-effective option for severe    psoriasis. Manag Care Interface. 2006; 19(1):33-36, 39.-   35. Beyer V, Wolverton S E. Recent trends in systemic psoriasis    treatment costs. Arch Dermatol. 2010; 146(1):46-54.-   36. Hakim D. Humira's Best-Selling Drug Formula: Start at a High    Price. Go Higher. New York Times 2018.-   37. Zhang P, Wu M X. A clinical review of phototherapy for    psoriasis. Lasers Med Sci. 2017.-   38. K170489-510(k) Clearance: Clarify Medical's Skylit Phototherapy    System. In: FDA, ed. Rockville, Md. 2017.-   39. Kemeny L, Csoma Z, Bagdi E, Banham A H, Krenacs L, Koreck A.    Targeted phototherapy of plaque-type psoriasis using ultraviolet    B-light-emitting diodes. Br J Dermatol. 2010; 163(1):167-173.-   40. Anderson E, Pell C, Dugan S, Martos A, Inventors; Luma    Therapeutics, assignee. Phototherapy dressing for treating    psoriasis. 2015.-   41. Calvo M E, Smirnov J C, Miguez H. Novel Approaches to Flexible    Visible Transparent Hybrid Films for Ultraviolet Protection. Journal    of Polymer Science Part B: Polymer Physics. 2012; 50:945-956.-   42. Meinhardt M, Krebs R, Anders A, Heinrich U, Tronnier H.    Wavelength-dependent penetration depths of ultraviolet radiation in    human skin. J Biomed Opt. 2008; 13(4):044030.-   43. Bohling A, Bielfeldt S, Himmelmann A, Keskin M, Wilhelm K P.    Comparison of the stratum corneum thickness measured in vivo with    confocal Raman spectroscopy and confocal reflectance microscopy.    Skin Res Technol. 2014; 20(1):50-57.-   44. Egawa M, Hirao T, Takahashi M. In vivo estimation of stratum    corneum thickness from water concentration profiles obtained with    Raman spectroscopy. Acta dermato-venereologica. 2007; 87(1):4-8.-   45. Vaillant L, Berson M, Machet L, Callens A, Pourcelot L,    Lorette G. Ultrasound imaging of psoriatic skin: a noninvasive    technique to evaluate treatment of psoriasis. Int J Dermatol. 1994;    33(11):786-790.-   46. Nizamoglu S, Gather M C, Humar M, et al. Bioabsorbable polymer    optical waveguides for deep-tissue photomedicine. Nat Commun. 2016;    7:10374.-   47. Biesman B S, Costner C. Evaluation of a transparent    perfluorodecalin-infused patch as an adjunct to laser-assisted    tattoo removal: A pivotal trial. Lasers Surg Med. 2017;    49(4):335-340.-   48. Biesman B S, O'Neil M P, Costner C. Rapid, high-fluence    multi-pass q-switched laser treatment of tattoos with a transparent    perfluorodecalin-infused patch: A pilot study. Lasers Surg Med.    2015; 47(8):613-618.-   49. Jansen E D, Pickett P M, Mackanos M A, Virostko J. Effect of    optical tissue clearing on spatial resolution and sensitivity of    bioluminescence imaging. J Biomed Opt. 2006; 11(4):041119.-   50. Liu Y, Norton J J, Qazi R, et al. Epidermal mechano-acoustic    sensing electronics for cardiovascular diagnostics and human-machine    interfaces. Sci Adv. 2016; 2(11):e1601185.-   51. Graaff R, Dassel A C, Koelink M H, de Mul F F, Aarnoudse J G,    Zijistra W G. Optical properties of human dermis in vitro and in    vivo. Appl Opt. 1993; 32(4):435-447.-   52. Makadia H K, Siegel S J. Poly Lactic-co-Glycolic Acid (PLGA) as    Biodegradable Controlled Drug Delivery Carrier. Polymers (Basel).    2011; 3(3):1377-1397.-   53. Lee J W, Xu R, Lee S, et al. Soft, thin skin-mounted power    management systems and their use in wireless thermography. Proc Natl    Acad Sci USA. 2016; 113(22):6131-6136.-   54. Greenhalgh D G, Lawless M B, Chew B B, Crone W A, Fein M E,    Palmieri T L. Temperature threshold for burn injury: an oximeter    safety study. J Burn Care Rehabil. 2004; 25(5):411-415.

UVB and UVA Biological Activity:

UVB (290 nm to 320 nm) induces apoptosis: programmed cell death in Tlymphocytes, keratinocytes and antigen presenting cells;Immunosuppressive: decreases TNF-α, IFN-γ, IL-17, IL-22 (allpro-inflammatory); Increases I L-10 (immunosuppressive cytokine); fieldeffect extends beyond clinical lesions; Side effects: skin erythema;skin cancer pathogenesis

UVA (320 nm to 400 nm): Induces apoptosis (B & T cells) via stimulationof superoxide anions and singlet oxygen species (depolarizesmitochondrial membrane); Unique in that it stimulates immediateapoptosis; Immunosuppressive by decreasing TNF-α, IL-12, IFN-γ (both arepro-inflammatory), and ICAM-1 (trafficking of immune cells to tissue);Anti-fibrotic by stimulating collagenase expression; Vasodilatory:stimulates release of nitric oxide (NO) from keratinocytes viaphotolabile intracutaneous NO metabolites which diffuse to capillaryvessels; Side effects: hyperpigmentation, photoaging, skin cancerpathogenesis. See, e.g., International Journal of Dermatology 2010, 49,623-630; J Cutan Med Surg 2013, 17, 6-12.

UVA liberates NO from photolabile intracutaneous NO metabolites. Afraction of the highly mobile NO diffuses toward the outer surface,where it escapes into the ambient atmosphere. (This fraction isdetectable with the airtight skin chamber.) Another NO fraction diffusesto deeper tissue layers, where it enters the capillary vessels andenhances local levels of RS-NO.

Low level light therapy (400 nm to 1400 nm) uses coherent (laser) ornon-coherent sources (LEDs); Growing evidence suggests coherent lightsources is not important for effect; Photobiomodulation mechanism noteven close to being elucidated fully; Biphasic behavior: “Goldilocks”problem; Absorption of light causes photo-dissociation of inhibitory NOfrom cytochrome c oxidase (respiratory chain transmembrane protein inmitochondria); This increases production of ATP; modulation of reactiveoxygen species; induces transcription factors (NF-kB, p53 cAMP, HIF);Seems to stimulate cellular metabolic activity; Immune cells e.g.lymphocytes, fibroblasts (produces collagen); Hemoglobin and melaninhave absorption bands 600-1070 nm; 600-700 nm for treating superficialtissue; 780-950 nm for deeper targets; Dosimetry: Irradiance and totalfluence delivered both important. See, e.g., Ann Biomed Eng. 2012February; 40(2): 516-533.

Medicine: appropriate wavelength selected for the target application;Dose: irradiance (mW/cm²), radiant exposure (J/cm²), pulse structure;Delivery: substrate, lateral spread and penetration depth; Heat:avoiding burns but using it as a secondary therapeutic modality; Targetsize: pLEDs for highly specific targets (single lesions); Larger arraysfor field treatments

Silicone Sheeting: Proposed Mechanisms in Wound healing; Silicone gelsfor scarring: typically lightly cross-linked PDMS chains (H-bridges);Ability to provide improved occlusion (thus extension of hydration)similar to normal skin; prevents evaporative water loss from theimpaired skin barrier; Transfer tension from the lateral edges of thewound bed to the silicone sheeting; Cooling effect of silicone reduceshyperemia and excess vasodilation; Free silicone diffuses to top layerof skin->unclear biological significance

Optical Tissue Clearing: Enables surface-application of biocompatiblesubstances to increase depth of light; Allows us greater opticalefficacy regardless of needle depth/density; Immersion of tissues intooptical-clearing agents (OCAs) that reduces the scattering of tissue andmake tissue more transparent; Glycerol (safe—biocompatible);Polyethylene glycol (commonly used in cosmetics); Perfluorodecalin; DMSO(biocompatible); Thiazone (chemical enhancer—some irritation)

Perfluorodecalin (PFD) Patch: Reduce Optical Scatter; Biocompatiblefluorocarbon liquid with high optical transparency (UV to IR); Lowsurface energy—rapidly wicks into porous materials; Used for detachedretinas; Absorbs half of its liquid volume of gaseousoxygen—investigated as a hemoglobin substitute; Refractive index ofskin: 1.44 to 1.42 depending on wavelength of light; Refractive index ofperfluorodecalin is 1.31; silicone gel is 1.40; good optical matching;Reduces optical scattering from keratinocytes—increases depth ofpenetration and energy delivery of light into the skin for tattooremoval; Peruorodecalin reduces optical scattering or the scattering oflight from microbubbles and skin cells, thus increasing the depth of thepenetration and energy delivery of light into the skin to shatter moreink particles trapped in the dermis

Light-Tissue Interactions: Flexible light therapy systems intimatelyconnected to skin reduces surface reflectance (tissue follows Snell'slaw); Coefficient μ_(a) (cm⁻¹) characterizes tissue absorption;Coefficient μ_(s) (cm⁻¹) characterizes tissue scatter (1/μ_(s)=mean freepath length until the next scattering event); Scattering is notisotropic in biological tissue; Forward scattering is predominant inbiological tissue; Anisotropy factor (g) ranges from 0 to 1; in tissuevary from 0.8 to 0.99:

μ′_(s)=μ_(s)(1−g)

The sum of μ_(s) and μ_(a) is called the total attenuation coefficientμ_(t)(cm⁻¹): μ_(t)=μ_(s)+μ_(a)

Transport theory: radiance L(r,s) of light at position r traveling indirection of unit vector s is decreased by absorption and scattering;Radiance is a radiometric measure: describes the amount of light thatpasses through or is emitted from a particular area; falls within agiven solid angle in a specific direction

${s \cdot {\nabla{L\left( {r,s} \right)}}} = {{{- \left( {\mu_{a} + \mu_{s}} \right)}{L\left( {r,s} \right)}} + {\mu_{s}{\int\limits_{4\; \pi}{{p\left( {s,s^{\prime}} \right)}{L\left( {r,s^{\prime}} \right)}d\; \omega^{\prime}}}}}$

Depth and Spread: Optimize microneedle length to enable full depthdelivery; Full treatment of dermis would be ˜2.5 mm depending onlocation (assumes 0.5 mm additional depth penetration); Consider optionsto minimize epidermal light exposure; deliver light in only at specificlayers; Maximize microneedle density to enable axial light delivery;Consider methods to allow light dissipation across length of needle

Pulse Structure: There have been some reports that pulse structure is animportant factor in LLLT; some have found better effects using 1 or 2 Hzpulses than 8 Hz or CW 830 nm laser on rat bone cells, but theunderlying mechanism for this effect is unclear

FIG. 36 Novel Microneedle Designs: Heat insulated and opaque at the top(0.1 mm) of the needle with thicker silicone coating->protects epidermisfrom injury and post-inflammatory hyperpigmentation; Heat conductive andtransparent bottom (0.1-0.5 mm) without coating->allows light delivery

The devices may be used in a medical or beauty application.

UVA+Waveguides: Morphea: A localized sclerotic disease that can causesignificant disfigurement among both pediatric and adult patients; UVAis highly effective but: Low availability of UVA units; Patients atincreased risk of skin cancer; systematic tanning; Clinical need:ability to apply UVA directly to the skin lesion; preferably in a homesetting with an auto-shut off mechanism.

UVA+Heat: Digital Ischemia: Distal perfusion issues remain a major unmetclinical need with pharmacological interventions of minimal benefit;Minimal modification of morphea UVA device; but optimize for more heatgeneration (DC drive the LEDs); Broad applications with tremendous unmetneeds; Applications: digital ischemia ulcers (systemic sclerosis,chronic renal failure, Raynaud's phenomena), vasopressor inducednecrosis (ICU setting), chronic vascular dysfunction (peripheralvascular disease), wound healing.

Cutaneous T-Cell Lymphoma: Malignant cells are exquisitely sensitive toNBUVB; it is standard of care for Stage IA (patch stage); The diseaseoften progresses to plaque/tumoral stage where NBUVB does not penetrate;Opportunity to utilize existing NBUVB systems but apply disposablemicroneedle waveguides on thicker tumoral lesions; Require greater depthand maximum tissue density.

Interventional Cardiology: UVA; microUVA embedded guidewire thatvasodilates as it extends into narrower coronary vessels; New class ofcoronary stents that will reduce restenosis without drugs. UV LEDs canbe vasodilatory, thereby providing a non-pharmacological method tovasodilate blood vessels.

LLLT+Waveguides+Heat: Pain; U.S. faces an opioid pain crisis; Pediatricpain remains poorly managed; Many localized pain syndromes; Longerwavelengths (˜800 to 900 nm) and higher output powers (to 100 mW) havebeen preferred in therapeutic devices for deeper tissue penetration; In2002, MicroLight Corp received 510K FDA clearance for a 830 nm diodelaser for the treatment of carpal tunnel syndrome; Acupuncture—growingbody of evidence for needle modulation of local pain; selected locationsof anatomical importance; Heat—long history as a therapeutic modality toreduce pain.

Low Level Light Therapy: Acne Vulgaris; Several systematic studiesdemonstrate LLLT efficacy in acne vulgaris; P. acnes destroyed viaactivation of protoporphyrin IX->ROS; Blue LED (400-500 nm)—77%improvement; Red LED (620-660 nm)—66% improvement; 10-200 mW/cm²; 2-60J/cm²; Better efficacy vs. 5% benzoyl peroxide; Target: deep, cysticlesions that occur 2-4 times monthly; painful—too deep for topicalmedications; Commonly occurs in pregnant women (hence need for safelight based system); Parameters: 10-200 mW/cm²; 2 J/cm²-60 J/cm².

Low Level Light Therapy: Periorobital Rhytides: Microneedling works tostimulate collagen neogenesis through the creation of micro-puncturewounds; Some studies show equivalence to fraxel laser ablation; Needlepitch, width, and length (0.5 mm to 4 mm) are all variable; Heat likelyplays a role in efficacy; Parameters: 10-200 mW/cm²; 2 J/cm²-60 J/cm²

Low Level Light Therapy: Periorbital Rhytides: Dissolvable single-usemicroneedle patches with LEDs for localized periorbital rhytides; Heatproduction is beneficial->one underlying mechanism of RF (but muchhigher heating here); consider addition of dye to disperse heat from theoptical energy. Challenge of dumping heat into the epidermis.Parameters: 10-200 mW/cm²; 2 J/cm²-60 J/cm²

NBUVB+Waveguides for Nails; Predominantly a penetration problem forphototherapy and topical medicines; Nail has significantly highermodulus; Implications for a wide range of nail diseases (major need)

Injectable, Cellular-Scale Optoelectronics with Applications forWireless Optogenetics, including flexible electronics on ballooncatheters

Opportunity space is vast: new treatment modality with broadapplications across clinical medicine and aesthetics, including:

UVA-1 waveguides for morphea.

UVA-1 waveguides+heat: distal perfusion problems.

UVA-1 for interventional cardiology applications.

LLLT waveguides+heat: regional cutaneous pain syndromes (or part ofnerve cuffs).

LLLT waveguides (485 nm & 640 nm): cystic acne lesions; Broadapplications for other deep infectious or inflammatory etiologies.

LLLT waveguides+heat: (830 nm) for periorbital rhytids; Broadapplications for other aesthetic problem areas.

NBUVB waveguides (311 nm) for nail psoriasis; Broad applications forother nail pathologies, rigid topographies (bone).

Scars: Keloids and Hypertrophic Scarring: $16 billion dollar problem:burns, piercings, accidents, post-surgical scars; Similarly, an abnormalhyper-fibrosis of injured skin; Current standard of care: silicone gelsheeting (3 RCTs in 186 patients show benefit); Small studies showingbenefit of infrared LED devices (805 nm); Mechanical effects:microneedling reduces and softens smaller acne scars; Our combination ofsilicone+light therapy+microneedles can be applied to both morphea andkeloids. 30 days with an infrared LED device (805-nm at 30 mW/cm2) andshowed significant improvement with no associated side effects asevidenced by improvements in VSS score, measurement of scar height byquantitative skin topography, and blinded clinical assessment ofphotographs. See, e.g., Barolet D, Boucher A. Prophylactic low-levellight therapy for the treatment of hypertrophic scars and keloids: acase series. Lasers in surgery and medicine. 2010; 42:597-601. [PubMed:20662038].

Example 4: Microneedle Light Guides for Integrated Wearable Devices toEnhance UV Delivery for Deep Skin Applications

There are many biological applications for light therapy, includingmedical therapeutic applications such as photothermal, photochemical(generation of free radicals and isomerization) and photobiological(cell stimulation). A common issue, however, is ensuring the appropriatelight wavelength and intensity is delivered to the desired tissueregion. On a skin surface, this is not an issue. In deeper tissue (e.g.,below the epidermal layer, such as at a depth greater than 50 μm, 75 μmor 150 μm to about 3 mm, or sub-ranges thereof), however, where theepidermis can act as a light barrier, this is a significant limitation.Conventional tissue illumination, such as by medical lamps, suffer fromthe fundamental limitation that both affected and healthy skin tissuesare exposed. This is particularly problematic for light that itself thathas a risk factor of adversely impacting healthy tissue, including UVlight.

The devices and methods presented herein address this issue by providinga type of waveguide to light that generates a well-defined exposureregion, including a three-dimensionally defined exposure region whereboth tissue depth and tissue area are well-controlled. Accordingly, anyof the devices and methods described herein may be characterized asproviding a controlled depth illumination, in terms of maximumpenetration depth from the surface (e.g., up to 5 mm, up to 4 mm, up to3 mm, up to 2 mm, and any subranges thereof). Furthermore, thecontrolled depth illumination may be described in terms of slice oftissue from the tissue surface, such as between 50 μm and 5 mm, 150 μmand 3 mm, or 150 μm and 2 mm, and any subranges thereof. Similarly, theillumination area footprint, which is dependent on the array ofmicroneedles footprint, can be controlled by the geometricalconfiguration, spacing and density of microneedles and optical lightsources. By activating every individual light source of an array ofoptical light sources, such as every LED that forms the overall lightsource, maximum footprint and intensity is achieved. By activating fewerlight sources in the array, the illumination footprint and/or intensityis controlled.

Accordingly, provided herein is a robust and powerful platform to tailorthe device and method to the application of interest, including adesired therapeutic area and/or therapeutic volume underlying a tissuesurface. In this manner, the light delivery is tailored to the desiredtissue, thereby minimizing light delivery to healthy tissue, anddecreasing power load requirement of the device. This provides afundamental biological improvement of minimizing unwanted exposure tohealthy tissue (even for enhanced light delivery in deep skin) andproviding the ability to power the device with an on-board power source(e.g., a battery) to facilitate device wearability and freedom ofmovement of the patient.

Fabrication scheme: An exemplary method of making an array of polymericmicroneedles is illustrated in FIG. 36. Provided herein are fabricationschemes that involve melt-molding of biocompatible polymers. A material,such as polydimethylsiloxane (PDMS), is patterned, including by laseretching to provide laser-ablated PDMS molds. Poly(lactic-co-glycolicacid) PLGA is placed on top of the mold, including PLGA pellets. Underhigh-temperature (about 180° C.) and vacuum (about 25 inches ofmercury), the PLGA flows into the mold recess features. Temperature isreduced and the PLGA material separated from the mold, thereby providinga microarray of microneedles. The molds may be reused.

FIG. 37 illustrates high quality microscale light guides are made fromthe fabrication scheme, including in the form of a 12×12 pyramidalmicroneedle array. There is negligible light loss in the guides (FIG.38).

The dimensions of the microneedles are readily tunable. FIG. 39 arephotographs of various densities of microneedles, including 44% (leftpanel), 56% (middle panel), and 64% (right panel) occupancy. Relativelylonger microneedles, such as 1 mm, can have increased occupancy.Microneedle length, however, is variable, including lengths between 0.5mm to 2 mm, for light delivery at target depths.

LEDs may be assembled on polyimide substrates with laser-cut orphotolithographically defined interconnects. FIG. 40 illustrates highperformance LEDs (e.g., UVA) having a footprint of 1.6×1.6×1.4 mm with acorresponding emission spectrum. Suitable optical power is generatedwith mild increases in temperatures.

The devices provided herein are characterized by well-defined lightintensity distribution, including a uniform light intensity (FIG.41A-41B) with high flexibility to facilitate conformal contact withcurvilinear surfaces (FIGS. 41C-41E). FIG. 42 further illustrates themechanical properties of the devices provided herein, suitable for soft,conformal contact with skin, with a bending radius of up to 3.5 mm (toppanel). Solvent treatments provide microneedles with extremely flexiblesubstrate layers (FIG. 42 middle and bottom panels). The relatively hardneedles (FIG. 43A) effectively penetrate skin (FIG. 43B), including withan insertion depth that averages 0.73±0.04 mm (n=10), which is over 70%of the needle length.

The dermal penetrating members provided herein enhance light delivery todeep tissue, including in deep skin. This is demonstrated in a gelphantom that is optically similar to human skin. Use of PLGAmicroneedles increase light penetration depth in turbid, skin-mimickingmedia compared to an identical control but without microneedles.Quantification of light intensity by Monte Carlo simulations (360 nmdecay in skin) is provided in FIG. 44. Greater than 3-times power isdelivered in deep skin (e.g., below 500 μm from the skin surface).

Computational models are validated using a UV photoactivated dye dopedphantom. Microneedles are inserted into the phantom and light generated.FIG. 45A-45B illustrates the experimentally-obtained result (FIG. 45A)matches the computationally determined results (FIG. 45B) for bothwithout microneedles (top panels) and with microneedles (bottom panels).

FIG. 46A-46B is a photograph of a device laminated on ex-plant humanskin tissue. FIGS. 46C-46D are experimental results of cell damage at13.5 J/cm² and 67.5 J/cm² for conventional lamps and the instantmicroneedle devices (MN). Cleaved caspase 3 is a biomarker for UVtoxicity. The UV LED patches deliver less light in the epidermis, with acorresponding lower level of damaged cells.

STATEMENTS REGARDING INCORPORATION BY REFERENCE AND VARIATIONS

All references throughout this application, for example patent documentsincluding issued or granted patents or equivalents; patent applicationpublications; and non-patent literature documents or other sourcematerial; are hereby incorporated by reference herein in theirentireties, as though individually incorporated by reference, to theextent each reference is at least partially not inconsistent with thedisclosure in this application (for example, a reference that ispartially inconsistent is incorporated by reference except for thepartially inconsistent portion of the reference).

The terms and expressions which have been employed herein are used asterms of description and not of limitation, and there is no intention inthe use of such terms and expressions of excluding any equivalents ofthe features shown and described or portions thereof, but it isrecognized that various modifications are possible within the scope ofthe invention claimed. Thus, it should be understood that although thepresent invention has been specifically disclosed by preferredembodiments, exemplary embodiments and optional features, modificationand variation of the concepts herein disclosed may be resorted to bythose skilled in the art, and that such modifications and variations areconsidered to be within the scope of this invention as defined by theappended claims. The specific embodiments provided herein are examplesof useful embodiments of the present invention and it will be apparentto one skilled in the art that the present invention may be carried outusing a large number of variations of the devices, device components,methods steps set forth in the present description. As will be obviousto one of skill in the art, methods and devices useful for the presentmethods can include a large number of optional composition andprocessing elements and steps.

When a group of substituents is disclosed herein, it is understood thatall individual members of that group and all subgroups, are disclosedseparately. When a Markush group or other grouping is used herein, allindividual members of the group and all combinations and subcombinationspossible of the group are intended to be individually included in thedisclosure.

Every formulation or combination of components described or exemplifiedherein can be used to practice the invention, unless otherwise stated.

Whenever a range is given in the specification, for example, a numericalrange, a wavelength range, a power range, a light intensity range, atransmission range, a length or width range, a pitch distance range, atemperature range, a time range, or a composition or concentrationrange, all intermediate ranges and subranges, as well as all individualvalues included in the ranges given are intended to be included in thedisclosure. It will be understood that any subranges or individualvalues in a range or subrange that are included in the descriptionherein can be excluded from the claims herein.

All patents and publications mentioned in the specification areindicative of the levels of skill of those skilled in the art to whichthe invention pertains. References cited herein are incorporated byreference herein in their entirety to indicate the state of the art asof their publication or filing date and it is intended that thisinformation can be employed herein, if needed, to exclude specificembodiments that are in the prior art. For example, when composition ofmatter are claimed, it should be understood that compounds known andavailable in the art prior to Applicant's invention, including compoundsfor which an enabling disclosure is provided in the references citedherein, are not intended to be included in the composition of matterclaims herein.

As used herein, “comprising” is synonymous with “including,”“containing,” or “characterized by,” and is inclusive or open-ended anddoes not exclude additional, unrecited elements or method steps. As usedherein, “consisting of” excludes any element, step, or ingredient notspecified in the claim element. As used herein, “consisting essentiallyof” does not exclude materials or steps that do not materially affectthe basic and novel characteristics of the claim. In each instanceherein any of the terms “comprising”, “consisting essentially of” and“consisting of” may be replaced with either of the other two terms. Theinvention illustratively described herein suitably may be practiced inthe absence of any element or elements, limitation or limitations whichis not specifically disclosed herein.

One of ordinary skill in the art will appreciate that startingmaterials, biological materials, reagents, synthetic methods,purification methods, analytical methods, assay methods, and biologicalmethods other than those specifically exemplified can be employed in thepractice of the invention without resort to undue experimentation. Allart-known functional equivalents, of any such materials and methods areintended to be included in this invention. The terms and expressionswhich have been employed are used as terms of description and not oflimitation, and there is no intention that in the use of such terms andexpressions of excluding any equivalents of the features shown anddescribed or portions thereof, but it is recognized that variousmodifications are possible within the scope of the invention claimed.Thus, it should be understood that although the present invention hasbeen specifically disclosed by preferred embodiments and optionalfeatures, modification and variation of the concepts herein disclosedmay be resorted to by those skilled in the art, and that suchmodifications and variations are considered to be within the scope ofthis invention as defined by the appended claims.

1-6. (canceled)
 7. The light delivery device of claim 8, wherein theoptical source delivers at least 0.1 mW/cm² and/or at least 10 mJ/cm² toa tissue during use.
 8. A conformable light delivery device forincreasing light penetration depth in a tissue, comprising: a microarrayof tissue penetrating members, each member having a distal end and aproximal end, wherein the tissue penetrating members are at leastpartially optically transparent to provide optical transmission througha surface that extends between the distal and proximal ends of eachtissue penetrating member; a substrate that supports the tissuepenetrating members, wherein the substrate is optionally a flexiblesubstrate; and an optical source in optical communication with themicroarray of tissue penetrating members, wherein the microarray and theoptical source are integrated or removably connected to each other. 9.The light delivery device of claim 8, wherein the optical source is atleast partially encapsulated in a transparent encapsulation layer. 10.The light delivery device of claim 8, wherein the microarray of tissuepenetrating members are configured to penetrate skin during use and toincrease a penetration depth of UV light into tissue by at least afactor of 1.1 compared to UV light exposed to the skin without themicroarray of tissue penetrating members.
 11. The light delivery deviceof claim 8, wherein each tissue penetrating member transmits at least90% of ultraviolet light or a desired subrange thereof. 12-14.(canceled)
 15. The light delivery device of claim 8, wherein the tissuepenetrating members have an optical property that is optically matchedto the optical source, wherein the optical property is selected from thegroup consisting of: optical transmission/output light spectrum; indexof refraction; scattering, absorption, emissivity, fluorescence, heatgeneration; and thermal relaxation time of tissue.
 16. (canceled) 17.(canceled)
 18. The light delivery device of claim 8, whereinultra-violet light is transmitted from the tissue penetrating membersthrough all side surfaces and the distal end to tissue surrounding thetissue penetrating members.
 19. (canceled)
 20. (canceled)
 21. The lightdelivery device of claim 8, wherein the device is flexible with a bulkbending stiffness selected so that the device is capable of conformingto a tissue surface during a light therapy application to reduce surfacereflection and increase light delivery to a target.
 22. The lightdelivery device of claim 21, wherein the reduced surface reflection isby the substrate having a composition that provides an index ofrefraction that is within 10% of an index of refraction of a materialfrom which the tissue penetrating members are formed.
 23. The lightdelivery device of claim 8, further comprising an optical dispersionelement in optical communication with the tissue penetrating members toincrease light dispersion and increase light intensity uniformity to atissue that surrounds the tissue penetrating members during use, whereinthe optical dispersion element comprises one or more of: a roughenedtissue penetrating member surface; an optical coating; a diffractiongrating; a waveguide; a chemically-modified tissue penetrating membersurface; a patterned optically opaque layer; lenses; or upconverting ordownconverting phosphors.
 24. The light delivery device of claim 8,having a light transmission footprint that is greater than or equal to0.2 cm².
 25. The light delivery device of claim 8, wherein the substratehas a bottom surface that supports the microarray of tissue penetratingmembers and a top surface that supports a plurality of optical sources.26. The light delivery device of claim 25, wherein the microarray oftissue penetrating members are optically aligned with the plurality ofoptical sources to provide substantially uniform light intensity to atissue that surrounds the microarray of tissue penetrating members. 27.A conformable light delivery device for increasing light penetrationdepth in a tissue, comprising: a microarray of tissue penetratingmembers, each member having a distal end and a proximal end, wherein thetissue penetrating members are at least partially optically transparentto provide optical transmission through a surface that extends betweenthe distal and proximal ends of each tissue penetrating member; and asubstrate that supports the tissue penetrating members, wherein thesubstrate is optionally a flexible substrate, wherein the microarray oftissue penetrating members is formed from a microarray material havingan index of refraction that is matched to an index of refraction of thesubstrate. 28-30. (canceled)
 31. The light delivery device of claim 34,wherein the bioactive agent comprises a coating on at least a portion ofa surface of the penetrating members.
 32. The light delivery device ofclaim 27, having a tissue penetrating member occupancy fraction (area ofmember base to area of substrate) that is greater than or equal to 10%.33. The light delivery device of claim 27, wherein the tissuepenetrating members have an effective Young's modulus selected towithstand stresses during insertion through a tissue surface withoutsubstantial deformation in a direction that decreases penetration depthin the tissue.
 34. The light delivery device of claim 27, wherein thedevice further comprises a bioactive agent releasably connected to themicroarray of tissue penetrating members, wherein the bioactive agent isactivated by light transmitted by the microarray of tissue penetratingmembers.
 35. The light delivery device of claim 27, wherein the deviceis integrated in a stent, a guidewire, a catheter, a balloon catheterfor use in a blood vessel; a subdermal implant; an orthopedic implant, aprosthesis, or a neurological implant.
 36. The light delivery device ofclaim 35, wherein the device is a conformable intra-arterial orintra-venous device and comprises a plurality of LEDs in opticalcommunication with the microarray of tissue penetrating members.
 37. Thelight delivery device of claim 36, wherein the LEDs are UV-emittingLEDs.
 38. The light delivery device of claim 37, wherein UV lightemitted by the UV-emitting LEDs is configured to vasodilate a bloodvessel.
 39. The light delivery device of claim 27, further comprising alight intensity modulator for controlling light intensity as a functionof depth from a tissue surface.
 40. The light delivery device of claim39, wherein the light intensity modulator comprises a non-transparentcoating extending from the tissue penetrating members' proximal end toreduce optical light intensity to a tissue surface region.
 41. The lightdelivery device of claim 40, wherein the non-transparent coating reducesUV light transmission and the tissue surface region corresponds to anepidermal layer.
 42. The light delivery device of claim 39, wherein thelight intensity output is focused toward or at the distal end of thetissue penetrating members.
 43. (canceled)
 44. (canceled)
 45. The lightdelivery device of claim 27, wherein the substrate further comprises asubstrate component that improves light delivery, wherein the substratecomponent comprises one or more of glycerol or perfluorodecalin.
 46. Aconformable light delivery device for increasing light penetration depthin a material comprising: a microarray of tissue penetrating membershaving a distal end and a proximal end, wherein the tissue penetratingmembers are at least partially optically transparent over a range ofwavelengths to provide optical transmission through a surface thatextends between the distal and proximal ends of each tissue penetratingmember; a flexible substrate having a top surface and a bottom surface,wherein the bottom surface supports the tissue penetrating members; aplurality of optical sources supported by the flexible substrate topsurface; an electronic circuit electrically connected to the pluralityof optical sources; and an encapsulation layer that at least partiallyencapsulates the plurality of optical sources and the electroniccircuit.
 47. The conformable light delivery device of claim 46, whereinthe microarray and flexible substrate are disposable and replaceable.48-50. (canceled)
 51. A method of providing light to a tissue, themethod comprising the steps of: providing a device of claim 27;conformally contacting the microarray with a tissue surface; insertingat least a portion of the microarray of tissue penetrating members intothe skin; transmitting light through the flexible substrate and themicroarray of tissue penetrating members to a tissue that surrounds themicroarray of tissue penetrating members, wherein the transmitting stepcomprises: energizing a plurality of LEDs connected to the substratesurface, wherein the LEDs have an emission maximum in the UV range or avisible portion of the electromagnetic spectrum.
 52. An injectabletherapeutic light delivery device comprising: a substrate; a tissuepenetrating member having a proximal end and a distal end, wherein theproximal end is supported by the substrate; a plurality of light sourcesoptically dispersed along a member wall that extends between the memberproximal and distal ends; wherein the tissue penetrating member andplurality of light sources are configured to penetrate a tissue toprovide controlled subsurface light intensity to tissue that surroundsthe tissue penetrating member.
 53. The device of claim 52, wherein thetissue penetrating member comprises a needle.
 54. The device of claim53, wherein the needle comprises an optically non-transparent material,including a metal, and the optical light sources are LEDs that aredistributed on a tissue-facing surface of the needle.
 55. The device ofclaim 54, wherein the LEDs are UV-emitting LEDs.
 56. The device of claim52, configured to treat cancer, including cutaneous T-cell lymphoma. 57.The device of claim 52, wherein the light delivery is of UVA or UVBlight at a tissue depth that is greater than or equal to 1 cm.
 58. Thedevice of claim 52, comprising a plurality of tissue penetratingmembers, wherein each tissue penetrating member has a plurality of lightsources optically dispersed along the member wall that extends betweenthe member proximal and distal ends.